U.S. patent number 5,607,934 [Application Number 08/397,043] was granted by the patent office on 1997-03-04 for piperazine derivatives and salts thereof.
This patent grant is currently assigned to Otsuka Pharmaceutical Co., Ltd.. Invention is credited to Toshiki Miyazaki, Masatoshi Morisue, Yoshimasa Nakano, Katsumi Tamura, Hitoshi Tone.
United States Patent |
5,607,934 |
Tone , et al. |
March 4, 1997 |
Piperazine derivatives and salts thereof
Abstract
Piperazine compounds and salts thereof having inhibitory effect
against superoxide radicals (O.sub.2.sup.-). The piperazine
compounds have the general formula: ##STR1## wherein R.sup.1 is a
lower alkyl group; R.sup.2 is a phenyl-lower alkyl group which may
have 1 to 3 substituents, on the phenyl ring, selected from the
group consisting of a hydroxyl group, a phenyl-lower alkoxy group,
a lower alkyl group, a lower alkoxy group and a halogen atom;
R.sup.3 is a hydrogen atom, a lower alkyl group or a phenyl-lower
alkyl group; and R.sup.4 is a hydroxyl group, a phenyl-lower alkoxy
group or a tetrahydropyranyloxy group.
Inventors: |
Tone; Hitoshi (Itano,
JP), Morisue; Masatoshi (Naruto, JP),
Tamura; Katsumi (Itano, JP), Miyazaki; Toshiki
(Tokushima, JP), Nakano; Yoshimasa (Itano,
JP) |
Assignee: |
Otsuka Pharmaceutical Co., Ltd.
(Tokyo, JP)
|
Family
ID: |
15948218 |
Appl.
No.: |
08/397,043 |
Filed: |
March 10, 1995 |
PCT
Filed: |
July 01, 1994 |
PCT No.: |
PCT/JP94/01071 |
371
Date: |
March 10, 1995 |
102(e)
Date: |
March 10, 1995 |
PCT
Pub. No.: |
WO95/02593 |
PCT
Pub. Date: |
January 26, 1995 |
Foreign Application Priority Data
|
|
|
|
|
Jul 13, 1993 [JP] |
|
|
5-172780 |
|
Current U.S.
Class: |
514/254.09;
544/368; 544/370; 544/385; 544/357; 514/253.01; 514/254.02;
514/254.1; 514/255.02; 514/254.05 |
Current CPC
Class: |
C07D
403/06 (20130101); A61P 35/00 (20180101); C07D
241/08 (20130101); C07D 417/12 (20130101); A61P
15/00 (20180101); A61P 3/00 (20180101); C07D
405/12 (20130101); A61P 13/02 (20180101) |
Current International
Class: |
C07D
403/06 (20060101); C07D 405/00 (20060101); C07D
241/00 (20060101); C07D 405/12 (20060101); C07D
417/00 (20060101); C07D 241/08 (20060101); C07D
417/12 (20060101); C07D 403/00 (20060101); A61K
031/495 (); C07D 241/02 (); C07D 403/02 (); C07D
241/04 () |
Field of
Search: |
;544/357,368,370,385
;514/252,253,255 |
Other References
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97729s. .
N-Hydroxytryptophan in the synthesis of natural products containing
oxidized dioxopiperazines. An approach to the neoechinulin and
sporidesmin series, Harry C. J. Ottenheijm et al., Chem. Abstr.,
vol.97 (1982) 6749a. .
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carboxylic esters, Chung Ch'i Shin et al., Chem. Abstr., vol. 74
(1971) 12570b. .
The .alpha..beta.-unsaturated carboxylic acid derivatives. IX.
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(1976) 17694m. .
.alpha..beta.-Unsaturated carboxylic acid derivatives. XIII. The
synthesis and configuration of alkyl 2-acyl-amino-2-alkenoates and
their cyclized 2,5-piperazinedione derivatives, Chung-Gi Shin,
Chem. Abstr., vol. 88 (1978) 190747m. .
Standardized one-and two-dimensional thin-layer chromatographic
methods for the identification of secondary metabolites in
Penicillium and other fungi, R. R. M. Paterson, Chem. Abstr., vol.
106 (1986), 29448v. .
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of mycotoxins and other secondary metabolites, Jens C. Frisvad,
Chem. Abstr., vol. 107 (1987) 36247c. .
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mycotoxins and other fungal metabolites based on alkylphenone
retention indexes and UV-VIS spectra (diode array detection), Jens
Frisvad et al., Chem. Abstr., vol. 107 (1987) 192376z. .
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retention indices of insecticidal extracts of Penicillium strains,
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Abstr., vol. 113 (1990) 128844x. .
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Yokomori et al., Chem. Abstr., vol. 112 (1990) 227120u. .
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et al., Chem. Abstr., vol. 111 (1990) 144490t. .
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of bergamottin and unbelliprenin, R. B. Bates et al., Chem. Abstr.,
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Etzionin, a new antifungal metabolite from a Red Sea tunicate,
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.
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al., Chem. Abstr., vol. 51 (1957) 3618. .
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al., Chem. Abstr., vol. 82 (1975) 167344v. .
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mycophenolic acid, A. J. Birch et al., Chem. Abstr., vol. 52 (1958)
3023..
|
Primary Examiner: Tsang; Cecilia
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner
Claims
We claim:
1. A piperazine compound having the general formula (1): ##STR78##
wherein R.sup.1 is a lower alkyl group;
R.sup.2 is a phenyl-lower alkyl group which may have, on the phenyl
ring, 1 to 3 substituents selected from the group consisting of a
hydroxyl group, a phenyl-lower alkoxy group, a lower alkyl group, a
lower alkoxy group and a halogen atom, an imidazolyl-substituted
lower alkyl group which may have one or more phenyl-lower alkyl
groups as substituents on the imidazolyl ring, or a group of the
formula: ##STR79## (wherein R.sup.5 and R.sup.6 are the same or
different, and are each a hydrogen atom, a benzothiazolyl group, or
a phenyl-lower alkyl group which may have, on the phenyl ring, 1 to
3 substituents selected from the group consisting of a lower alkoxy
group, a phenyl-lower alkoxy group, a lower alkyl group and a
hydroxyl group, further, said R.sup.5 and R.sup.6 and the adjacent
nitrogen atom being bonded thereto, together with or without
another nitrogen atom or an oxygen atom, may form a 5- to
6-membered saturated heterocyclic group; said heterocyclic group
may have, as substituents, one or more phenyl groups which may have
one or more lower alkoxy groups as substituents on the phenyl
ring);
R.sup.3 is a hydrogen atom, a lower alkyl group or a phenyl-lower
alkyl group; and
R.sup.4 is a hydroxyl group, a phenyl-lower alkoxy group or a
tetrahydropyranyloxy group;
and pharmaceutically acceptable salts thereof.
2. A piperazine compound having the general formula (2): ##STR80##
wherein R.sup.7 is a lower alkyl group, a phenyl-lower alkyl group
which may have, on the phenyl ring, one or more substituents
selected from the group consisting of a hydroxyl group and a
phenyl-lower alkoxy group, a lower alkylthio group- substituted
lower alkyl group, a phenyl-lower alkoxy group- substituted lower
alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl
group- substituted lower alkyl group or a hydroxyl
group-substituted lower alkyl group;
R.sup.8 is a hydrogen atom; further R.sup.7 and R.sup.8 may form a
trimethylene group by combining together; and
R.sup.9 is a hydroxyl group or a phenyl-lower alkoxy group; and
pharmaceutically acceptable salts thereof.
3. The piperazine compound or salt thereof according to claim 1,
wherein R.sup.2 is a phenyl-lower alkyl group which may have, on
the phenyl ring, 1 to 3 substituents selected from the group
consisting of a hydroxyl group, a phenyl-lower alkoxyl group, a
lower alkyl group, a lower alkoxy group and a halogen atom.
4. The piperazine compound or salt thereof according to claim 1,
wherein R.sup.2 is an imidazolyl-substituted lower alkyl group
which may have one or more phenyl-lower alkyl groups as
substituents on the imidazolyl ring.
5. The piperazine compound or salt thereof according to claim 1,
wherein R.sup.2 is a group of the formula: ##STR81##
6. The piperazine compound or salt thereof according to claim 3,
wherein R.sup.3 is a hydrogen atom.
7. The piperazine compound or salt thereof according to claim 3,
wherein R.sup.3 is a lower alkyl group or a phenyl-lower alkyl
group.
8. The piperazine compound or salt thereof according to claim 4,
wherein R.sup.3 is a hydrogen atom.
9. The piperazine compound or salt thereof according to claim 4,
wherein R.sup.3 is a lower alkyl group or a phenyl-lower alkyl
group.
10. The piperazine compound or salt thereof according to claim 5,
wherein R.sup.3 is a hydrogen atom.
11. The piperazine compound or salt thereof according to claim 5,
wherein R.sup.3 is a lower alkyl group or a phenyl-lower alkyl
group.
12. The piperazine compound or salt thereof according to any one of
claims 6 to 11, wherein R.sup.4 is a hydroxyl group.
13. The piperazine compound or salt thereof according to any one of
claims 6 to 11, wherein R.sup.4 is a phenyl-lower alkoxy group or a
tetrahydropyranyloxy group.
14. The piperazine compound or salt thereof according to claim 2,
wherein R.sup.7 is a lower alkoxycarbonyl group-substituted lower
alkyl group.
15. The piperazine compound or salt thereof according to claim 2,
wherein R.sup.7 and R.sup.8 form a trimethylene group by combining
together.
16. The piperazine compound or salt thereof according to claim 2,
wherein R.sup.7 is a lower alkyl group, a phenyl-lower alkyl group
which may have, on the phenyl ring, one or more substituents
selected from the group consisting of a hydroxyl group and a
phenyl-lower alkoxyl group, a lower alkylthio group-substituted
lower alkyl group, a phenyl-lower alkoxy group-substituted lower
alkyl group, a lower alkoxycarbonyl group, or a hydroxyl
group-substituted lower alkyl group.
17. The piperazine compound or salt thereof according to any one of
claims 14 to 16, wherein R.sup.9 is a hydroxyl group.
18. The piperazine compound or salt thereof according to any one of
claims 14 to 16, wherein R.sup.9 is a phenyl-lower alkoxy
group.
19. (3RS,
6RS)-1-Hydroxy-3-(3,5-di-tert-butyl-4-hydroxybenzyl)-6-isobutylpiperazin-2
,5-dione.
20. (3RS,
6SR)-1-Hydroxy-3-(3,5-di-tert-butyl-4-hydroxybenzyl)-6-isobutylpiperazin-2
,5-dione.
21. (3RS,
6RS)-1-Hydroxy-6-(3-indolylmethyl)-3-ethoxycarbonylmethylpiperazin-2,5-dio
ne.
22. (3RS,
6SR)-1-Hydroxy-6-(3-indolylmethyl)-3-ethoxycarbonylmethylpiperazin-2,5-dio
ne.
23. (3S,
6R)-1-Hydroxy-6-(3-indolylmethyl)-3-ethoxycarbonylmethylpiperazin-2,5-dion
e.
24. A pharmaceutical composition for inhibiting superoxide radicals
which contains, as the active ingredient, a therapeutically
effective amount of a piperazine compound or salt thereof of claim
1 and a pharmaceutically acceptable carrier.
25. A pharmaceutical composition for inhibiting superoxide radicals
which contains, as the active ingredient, a therapeutically
effective amount of a piperazine compound or salt thereof of claim
2 and a pharmaceutically acceptable carrier.
26. A pharmaceutical composition for preventing and treating
diseases or symptoms being caused by superoxide radicals which
contains, as the active ingredient, a therapeutically effective
amount of a piperazine compound or salt thereof of claim 1 and a
pharmaceutically acceptable carrier.
27. A pharmaceutical composition for preventing and treating
diseases or symptoms being caused by superoxide radicals which
contains, as the active ingredient, a therapeutically effective
amount of a piperazine compound or salt thereof of claim 2 and a
pharmaceutically acceptable carrier.
28. A pharmaceutical composition for preventing and treating
nephritis which contains, as the active ingredient, a
therapeutically effective amount of a piperazine compound or salt
thereof of claim 1 and a pharmaceutically acceptable carrier.
29. A pharmaceutical composition for preventing and treating
nephritis which contains, as the active ingredient, a
therapeutically effective amount of a piperazine compound or salt
thereof of claim 2 and a pharmaceutically acceptable carrier.
30. Process for preparing a piperazine compound of the formula:
##STR82## wherein R.sup.1 is a lower alkyl group;
R.sup.3 is a hydrogen atom, a lower alkyl group or a phenyl-lower
alkyl group;
R.sup.4 is a hydroxyl group, a phenyl-lower alkoxy group or a
tetrahydropyranyloxy group; and
R.sup.5 and R.sup.6 are the same or different, and are each a
hydrogen atom, a benzothiazolyl group, or a phenyl-lower alkyl
group which may have, on the phenyl ring, 1 to 3 substituents
selected from the group consisting of a lower alkoxy group, a
phenyl-lower alkoxy group, a lower alkyl group and a hydroxyl
group; further, said R.sup.5 and R.sup.6 and the adjacent nitrogen
atom being bonded thereto, together with or without another
nitrogen atom or an oxygen atom, may form a 5- to 6-membered
saturated heterocyclic group; said heterocyclic group may have, as
substituents, one or more phenyl groups which may have one or more
lower alkoxy groups as substituents on the phenyl ring;
by reacting a compound of the formula: ##STR83## (wherein R.sup.1,
R.sup.3 and R.sup.4 are the same as defined above) with a compound
of the formula: ##STR84## (wherein R.sup.5 and R.sup.6 are the same
as defined above).
Description
This application is a 371 of PCT/JP94/01071, filed Jul. 1,
1994.
FIELD OF THE INDUSTRIAL UTILIZATION
The present invention relates to novel piperazine derivatives and
salts thereof.
BACKGROUND ART
There have been known some piperazine derivatives having chemical
structural formulae similar to those of the piperazine derivatives
of the present invention, from the following prior art references,
i.e. EP-A2-303250 and U.S. Pat. No. 5,021,419.
DISCLOSURE OF THE INVENTION
The present invention provides piperazine derivatives and salts
thereof, which are novel and are not known in prior art references.
Said piperazine derivatives are represented by the following
general formulae (1) and (2): ##STR2## wherein R.sup.1 is a lower
alkyl group;
R.sup.2 is a phenyl-lower alkyl group which may have, on the phenyl
ring, 1 to 3 substituents selected from the group consisting of a
hydroxyl group, a phenyl-lower alkoxy group, a lower alkyl group, a
lower alkoxy group and a halogen atom, an imidazolyl-substituted
lower alkyl group which may have phenyl-lower alkyl group(s) as the
substituent(s) on the imidazolyl ring, or a group of the formula:
##STR3## (wherein R.sup.5 and R.sup.6 are the same or different and
are each a hydrogen atom, a benzothiazolyl group, or a phenyl-lower
alkyl group which may have, on the phenyl ring, 1 to 3 substituents
selected from the group consisting of a lower alkoxy group, a
phenyl-lower alkoxy group, a lower alkyl group and a hydroxyl
group; further, said R.sup.5 and R.sup.6 and the adjacent nitrogen
atom bonding thereto may form, together with or without other
nitrogen atom or an oxygen atom, a 5- to 6-membered saturated
heterocyclic group; said heterocyclic group may have, as the
substituent(s), phenyl group(s) which may have lower alkoxy
group(s) as the substituent(s) on the phenyl ring);
R.sup.3 is a hydrogen atom, a lower alkyl group or a phenyl-lower
alkyl group; and
R.sup.4 is a hydroxyl group, a phenyl-lower alkoxy group or a
tetrahydropyranyloxy group; and ##STR4## wherein R.sup.7 is a lower
alkyl group, a phenyl-lower alkyl group which may have, on the
phenyl ring, substituent(s) selected from the group consisting of a
hydroxyl group and a phenyl-lower alkoxy group, a lower alkylthio
group-substituted lower alkyl group, a phenyl-lower alkoxy
group-substituted lower alkyl group, a lower alkoxycarbonyl group,
a lower alkoxycarbonyl group-substituted lower alkyl group or a
hydroxyl group-substituted lower alkyl group;
R.sup.8 is a hydrogen atom; further R.sup.7 and R.sup.8 may form a
trimethylene group together; and
R.sup.9 is a hydroxyl group or a phenyl-lower alkoxy group.
The piperazine derivatives represented by the above general
formulae (1) and (2) and the salts thereof according to the present
invention possess an inhibitory effect against superoxide radical
(O.sub.2.sup.-) released from the macrophage cells of guinea pig by
stimulation, and also possess an anti-albuminuria activity in
Masugi nephritis. Thus, the piperazine derivatives represented by
general formulae (1) and (2) and the salts thereof are useful
agents for preventing and treating various diseases caused by the
above-mentioned superoxide radical, for example, diseases of
autoimmunity (e.g. rheumatoid arthritis), artheriosclerosis,
ischemic heart disease, transient cerebral ischematic attack,
hepatic insufficiency and renal insufficiency. They are also useful
agents for preventing and treating the nephritis in various
clinical fields.
In addition to the above, the piperazine derivatives of general
formulae (1) and (2) and the salts thereof also possess an
inhibitory effect against the proliferation of Mesangium cells
which are closely related to the development of the nephritis;
thus, they are useful agents for preventing and treating the
proliferative nephritis.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the present specification, each of the substituents in general
formulae (1) and (2) is specifically as follows.
The lower alkoxy group can be exemplified by straight-chain or
branched-chain alkoxy groups having 1 to 6 carbon atoms, such as
methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy,
pentyloxy and hexyloxy groups and the like.
The lower alkyl group can be exemplified by straight-chain or
branched-chain alkyl groups having 1 to 6 carbon atoms, such as
methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and
hexyl groups and the like.
The phenyl-lower alkyl group which may have, on the phenyl ring, 1
to 3 substituents selected from the group consisting of a hydroxyl
group, a phenyl-lower alkoxy group, a lower alkyl group, a lower
alkoxy group and a halogen atom, can be exemplified by phenylalkyl
groups in which the alkyl moiety is a straight-chain or branched
chain alkyl group having 1 to 6 carbon atoms and which may have, on
the phenyl ring, 1 to 3 substituents selected from the group
consisting of a hydroxyl group, a phenylalkoxy group in which the
alkoxy moiety is a straight-chain or branched-chain alkoxy group
having 1 to 6 carbon atoms, a straight-chain or branched-chain
alkyl group having 1 to 6 carbon atoms, a straight-chain or
branched-chain alkoxy group having 1 to 6 carbon atoms and a
halogen atom, such as benzyl, 2-phenylethyl, 1-phenylethyl,
3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl,
5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl,
2-(3-methoxyphenyl)ethyl, 1-(4-methoxyphenyl)ethyl,
2-methoxybenzyl, 3-(2-ethoxyphenyl)propyl, 4-(3ethoxyphenyl)butyl,
1,1-dimethyl-2-(4-ethoxyphenyl)ethyl, 5-(4-isopropoxyphenyl)pentyl,
6-(4-hexyloxyphenyl)hexyl, 3,4-dimethoxybenzyl,
3,4,5-trimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl,
1-phenyl-1-hydroxymethyl, 2-hydroxy-2-phenylethyl,
3-hydroxy-3-phenylpropyl, 4-hydroxy-4-phenylbutyl,
1,1-dimethyl-2-hydroxy-2-phenylethyl, 5-hydroxy-5-phenylpentyl,
6-phenyl-6-hydroxyhexyl, 2-methyl-3-phenyl-3-hydroxypropyl,
2-(4-methoxyphenyl)-2-hydroxyethyl,
2-(3-ethoxyphenyl)-2-hydroxyethyl,
4-hydroxy-4-(3,4-dimethoxyphenyl)butyl, 3-methoxybenzyl,
4-methoxybenzyl, 2,4-diethoxybenzyl, 2,3-dimethoxybenzyl,
2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, 4-benzyloxybenzyl,
2-(3-benzyloxyphenyl)ethyl, 1-(2-benzyloxyphenyl)ethyl,
3-[2-(2-phenylethoxy)phenyl]propyl,
4-[3-(3-phenylpropoxy)phenyl]butyl,
1,1-dimethyl-2-[4-(4-phenylbutoxy)phenyl]ethyl,
5-[2-(5-phenylpentyloxy)phenyl]pentyl,
6-[3-(6-phenylhexyloxy)phenyl]hexyl, 2-hydroxybenzyl,
4-hydroxybenzyl, 2-(3-hydroxyphenyl)ethyl, 1- (4-hydroxyphenyl)
ethyl, 3-(2-hydroxyphenyl)propyl, 4- (3-hydroxyphenyl) butyl,
5-(2-hydroxyphenyl)pentyl, 6- (3-hydroxyphenyl) hexyl,
3,4-dihydroxybenzyl, 3,4,5-trihydroxybenzyl,
3,5-dimethoxy-4-benzyloxybenzyl, 3,5-dimethoxy-4-hydroxybenzyl,
3,5-di-tert-butoxy-4-benzyloxybenzyl,
3,5-di-tert-butoxy-4-hydroxybenzyl, 2-methylbenzyl,
2-(3-methylphenyl)ethyl, 1-(4-methylphenyl)ethyl,
3-(2-ethylphenyl)propyl, 4-(3ethylphenyl)butyl,
1,1-dimethyl-2-(4-ethylphenyl)ethyl, 5-(4-isopropylphenyl)pentyl,
6-(4-hexylphenyl)hexyl, 3,4-dimethylbenzyl, 3,4,5-trimethylbenzyl,
2,5-dimethylbenzyl, 2-chlorobenzyl, 2-(3-chlorophenyl)ethyl,
2-fluorobenzyl, 1-(4-chlorophenyl)ethyl, 3-(2-fluorophenyl)propyl,
4-(3-fluorophenyl)butyl, 5-(4-fluorophenyl)pentyl,
1,1-dimethyl-2-(2-bromophenyl)ethyl, 6-(3-bromophenyl)hexyl,
4-bromobenzyl, 2-(2-iodophenyl)ethyl, 1-(3-iodophenyl)ethyl,
3-(4-iodophenyl)propyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl,
2,6-dichlorobenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl,
3,4-difluorobenzyl, 3,5-dibromobenzyl, 3,4,5-trichlorobenzyl,
3,5-dichloro-4-hydroxybenzyl, 3,5-dimethyl-4-hydroxybenzyl and
2-methoxy-3-chlorobenzyl groups and the like.
The lower alkoxycarbonyl group can be exemplified by straight-chain
or branched-chain alkoxycarbonyl groups having 1 to 6 carbon atoms,
such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,
pentyloxycarbonyl and hexyloxycarbonyl groups and the like.
The phenyl-lower alkoxy group can be exemplified by phenylalkoxy
groups in which the alkoxy moiety is a straight-chain or
branched-chain alkoxy group having 1 to 6 carbon atoms, such as
benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy,
4-phenylbutoxy, 1,1-dimethyl-2-phenylethoxy, 5-phenylpentyloxy,
6-phenylhexyloxy and 2-methyl-3-phenylpropoxy groups and the
like.
As the halogen atom, there can be cited, for example, a fluorine
atom, a chlorine atom, a bromine atom and an iodine atom.
The phenyl-lower alkyl group can be exemplified by phenylalkyl
groups in which the alkyl moiety is a straight-chain or
branched-chain alkyl group of 1 to 6 carbon atoms, such as benzyl,
2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,
1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl and
2-methyl-3-phenylpropyl groups and the like.
The imidazolyl-substituted lower alkyl group which may have
phenyl-lower alkyl group(s) as the substituent(s) on the imidazolyl
ring, can be exemplified by imidazolyl-substituted lower alkyl
groups in which the lower alkyl moiety is a straight-chain or
branched-chain alkyl group of 1 to 6 carbon atoms and which may
have, as the substituent(s) on the imidazolyl ring, phenylalkyl
group(s) whose alkyl moiety is a straight-chain or branched-chain
alkyl group having 1 to 6 carbon atoms, such as
(4-imidazolyl)methyl, 2-(2-imidazolyl)ethyl, 1-(4-imidazolyl)ethyl,
3-(5-imidazolyl)propyl, 4-(2-imidazolyl)butyl,
1,1-dimethyl-2-(4-imidazolyl)ethyl, 5-(5-imidazolyl)pentyl,
6-(2imidazolyl)hexyl, 2-methyl-3-(4-imidazolyl)propyl,
(1-benzyl-4-imidazolyl)methyl,
2-[1-(2-phenylethyl)-4imidazolyl]ethyl,
1-[5-(1-phenylethyl)-2-imidazolyl]ethyl,
3-[1-(3-phenylpropyl)-5-imidazolyl]propyl,
4-[4(4-phenylbutyl)-2-imidazolyl]butyl, 5-[2-(5-phenyl-
pentyl)-4-imidazolyl]pentyl and
6-[1-(6-phenylhexyl)-4imidazolyl]hexyl groups and the like.
The phenyl-lower alkyl group which may have, on the phenyl ring, 1
to 3 substituents selected from the group consisting of a lower
alkoxy group, a phenyl-lower alkoxy group, a lower alkyl group and
a hydroxyl group, can be exemplified by phenylalkyl groups in which
the alkyl moiety is a straight-chain or branched-chain alkyl group
of 1 to 6 carbon atoms and which may have, on the phenyl ring, 1 to
3 substituents selected from the group consisting of a
straight-chain or branched-chain alkoxy group of 1 to 6 carbon
atoms, a phenylalkoxy group in which the alkoxy moiety is a
straight-chain or branched-chain alkoxy group of 1 to 6 carbon
atoms, a straight-chain or branched-chain alkyl group of 1 to 6
carbon atoms and a hydroxyl group, such as benzyl, 2-phenylethyl,
1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,
1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl,
2-methyl-3-phenylpropyl, 2-methoxybenzyl, 3-methoxybenzyl,
4-methoxybenzyl, 2-(3-methoxyphenyl)ethyl,
1-(4-methoxyphenyl)ethyl, 2-methoxybenzyl,
3-(2-ethoxyphenyl)propyl, 4-(3-ethoxyphenyl)butyl,
1,1-dimethyl-2-(4-ethoxyphenyl)ethyl, 5-(4-isopropoxyphenyl)pentyl,
6-(4-hexyloxyphenyl)hexyl, 3,4-dimethoxybenzyl,
3,4,5-trimethoxybenzyl, 2,5-dimethoxybenzyl, 2,4-diethoxybenzyl,
2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl,
4-benzyloxybenzyl, 2-(3-benzyloxyphenyl)ethyl,
1-(2-benzyloxyphenyl)ethyl, 3-[2-(2-phenylethoxy)phenyl]propyl,
4-[3-(3-phenylpropoxy)phenyl]butyl,
1,1-dimethyl-2-[4-(4-phenylbutoxy)phenyl]ethyl,
5-[2-(5-phenylpentyloxy)phenyl]pentyl,
6-[3-(6-phenylhexyloxy)phenyl]hexyl, 2-hydroxybenzyl,
2-(3-hydroxyphenyl)ethyl, 1-(4-hydroxyphenyl)ethyl,
3-(2-hydroxyphenyl)propyl, 4-(3-hydroxyphenyl)butyl,
5-(2-hydroxyphenyl)pentyl, 6-(3-hydroxyphenyl)hexyl,
3,4-dihydroxybenzyl, 3,4,5-trihydroxybenzyl,
3,5-dimethoxy-4-benzyloxybenzyl, 3,5-dimethoxy-4-hydroxybenzyl,
3,5-di-tert-butoxy-4-hydroxybenzyl, 2-methylbenzyl,
2-(3-methylphenyl)ethyl, 1-(4-methylphenyl)ethyl,
3-(2-ethylphenyl)propyl, 4-(3-ethylphenyl)butyl,
1,1-dimethyl-2-(4-ethylphenyl)ethyl, 5-(4-isopropylphenyl)pentyl,
6-(4-hexylphenyl)hexyl, 3,4-dimethylbenzyl, 3,4,5-trimethylbenzyl,
3,5-di-tert-butyl-4-hydroxybenzyl and
3,5-di-tert-butyl-4-benzyloxybenzyl groups and the like.
The 5- or 6-membered saturated heterocyclic group formed by
R.sup.5, R.sup.6 and the adjacent nitrogen atom bonding thereto,
together with or without other nitrogen atom or an oxygen atom, can
be exemplified by piperazinyl, pyrrolidinyl, morpholinyl and
piperidinyl groups and the like.
The above heterocyclic group which has, as the substituent(s),
phenyl group(s) which may have lower alkoxy group(s) as the
substituent(s) on the phenyl ring, can be exemplified by the above
heterocyclic groups which have, as the substituent(s), phenyl
group(s) which may have 1 to 3 straight-chain or branched-chain
alkoxy groups of 1 to 6 carbon atoms as the substituent(s) on the
phenyl ring, such as 4-(2-methoxyphenyl)piperazinyl,
4-(2,4-dimethoxyphenyl)piperidinyl,
3-(2,3,4-trimethoxyphenyl)morpholinyl,
2-(3-methoxyphenyl)pyrrolidinyl, 2-phenylpiperidinyl,
2-(2-ethoxyphenyl)piperazinyl, 3-(3-propoxyphenyl)piperidinyl,
2-(4-butoxyphenyl)morpholino, 3-(2-pentyloxyphenyl)pyrrolidinyl and
3-(4-hexyloxyphenyl)piperazinyl groups and the like.
The phenyl group which may have lower alkoxy group(s) as the
substituent(s) on the phenyl ring, can be exemplified by phenyl
groups which may have, as the substituent(s) on the phenyl ring, 1
to 3 straight-chain or branched-chain alkoxy groups of 1 to 6
carbon atoms, such as phenyl, 2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl,
3-isopropoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl,
2,5-dimethoxyphenyl and 3,4,5-trimethoxyphenyl groups and the
like.
The phenyl-lower alkyl group which may have, on the phenyl ring,
substituent(s) selected from the group consisting of a hydroxyl
group and a phenyl-lower alkoxy group, can be exemplified by
phenylalkyl groups in which the alkyl moiety is a straight-chain or
branched-chain alkyl group of 1 to 6 carbon atoms and which may
have, on the phenyl ring, 1 to 3 substituents selected from the
group consisting of a hydroxyl group and a phenylalkoxy group whose
alkoxy moiety is a straight-chain or branched-chain alkoxy group of
1 to 6 carbon atoms, such as 2-hydroxybenzyl, 3-hydroxybenzyl,
4-hydroxybenzyl, 2-(3-hydroxyphenyl)ethyl,
1-(4-hydroxyphenyl)ethyl, 3-(2-hydroxyphenyl)propyl,
4-(3-hydroxyphenyl)butyl, 5-(2-hydroxyphenyl)pentyl,
6-(3-hydroxyphenyl)hexyl, 3,4-dihydroxybenzyl,
3,4,5-trihydroxybenzyl, 4-benzyloxybenzyl,
2-(3-benzyloxyphenyl)ethyl, 1-(2-benzyloxyphenyl)ethyl,
3-[2-(2-phenylethoxy)phenyl]propyl,
4-[3-(3-phenylpropoxy)phenyl]butyl,
1,1-dimethyl-2-[4-(4-phenylbutoxy)phenyl]ethyl,
5-[2-(5-phenylpentyloxy)phenyl]pentyl and
6-[3-(6-phenylhexyloxy)phenyl]hexyl groups and the like.
The lower alkylthio group-substituted lower alkyl group can be
exemplified by alkylthio group-substituted alkyl groups in which
the alkylthio moiety is a straight-chain or branched-chain
alkylthio group of 1 to 6 carbon atoms and the alkyl moiety is a
straight-chain or branched-chain alkyl group of 1 to 6 carbon
atoms, such as methylthiomethyl, 2-(methylthio)ethyl,
1-(ethylthio)ethyl, 3-(propylthio)propyl, 4-(n-butylthio)butyl,
5-(pentylthio)pentyl and 6-(hexylthio)hexyl groups and the
like.
The phenyl-lower alkoxy group-substituted lower alkyl group can be
exemplified by phenylalkoxy group-substituted alkyl groups in which
the alkoxy moiety is a straight-chain or branched-chain alkoxy
group of 1 to 6 carbon atoms and the alkyl moiety is a
straight-chain or branched-chain alkyl group of 1 to 6 carbon
atoms, such as benzyloxymethyl, 2-(2-phenylethoxy)ethyl,
1-(1-phenylethoxy)ethyl, 3-(3-phenylpropoxy)propyl,
4-(4-phenylbutoxy)butyl, 5-(5-phenylpentyloxy)pentyl,
6-(6-phenylhexyloxy)hexyl, (2-methyl-3-phenylpropoxy)methyl and
(1,1-dimethyl-2-phenylethoxy)methyl groups and the like.
The lower alkoxycarbonyl-lower alkyl group can be exemplified by
alkoxycarbonylalkyl groups in which the alkoxy moiety is a
straight-chain or branched-chain alkoxy group of 1 to 6 carbon
atoms and the alkyl moiety is a straight-chain or branched-chain
alkyl group of 1 to 6 carbon atoms, such as methoxycarbonylmethyl,
3-methoxycarbonylpropyl, ethoxycarbonylmethyl,
4-ethoxycarbonylbutyl, 1-ethoxycarbonylethyl,
1-methoxycarbonylethyl, 6-propoxycarbonylhexyl,
5-isopropoxycarbonylpentyl, 1,1-dimethyl-2-butoxycarbonylethyl,
2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl and
hexyloxycarbonylmethyl groups and the like.
The hydroxyl group-substituted lower alkyl group can be exemplified
by straight-chain or branched-chain alkyl groups of 1 to 6 carbon
atoms having 1 to 3 hydroxyl groups as the substituent(s), such as
hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,
2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl,
5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl,
1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, 2,3-dihydroxyethyl,
3,4-dihydroxybutyl and 5,6-dihydroxyhexyl groups and the like.
The piperazine derivatives represented by general formulae (1) and
(2) according to the present invention can be produced by various
processes. Preferable examples of the processes are shown below.
##STR5## (wherein R.sup.1, R.sup.3, R.sup.4, R.sup.5 and R.sup.6
are the same as defined above).
The reaction between the compound (3) and the compound (4) is
carried out by an ordinary amido bond formation reaction. The amido
bond formation reaction can be carried out by various known
processes, for example, (a) a mixed acid anhydride process which
comprises, for example, reacting the carboxylic acid (3) with an
alkyl halocarboxylate and then reacting the resulting mixed acid
anhydride with the amine (4), (b) an active ester process which
comprises, for example, converting the carboxylic acid (3) into an
active ester (e.g. p-nitrophenyl ester, succinimidyl ester or
benzotiazol-1-yl ester) and then reacting the active ester with the
amine (4), (c) a carbodiimide process which comprises condensing
the carboxylic acid (3) and the amine (4) in the presence of an
activating agent such as dicyclohexylcarbodiimide,
N,N-carbonyldiimidazole or the like, and (d) other processes. The
other processes (d) include, for example, a process which comprises
converting the carboxylic acid (3) into a carboxylic acid anhydride
by the use of a dehydrating agent (e.g. acetic anhydride) and then
reacting the carboxylic acid anhydride with the amine (4), and a
process which comprises reacting the carboxylic acid (3) with a
lower alcohol and then reacting the resulting ester with the amine
(4) at a high pressure at a high temperature. There may also be
employed a process which comprises activating the carboxylic acid
(3) with a phosphorus compound such as triphenylphosphine, diethyl
chlorophosphate or the like and then reacting the resulting
material with the amine (4). There may also be employed a process
which comprises activating the carboxylic acid (3) with an
acetylene compound such as trimethylsilylethoxyacetylene or the
like and then reacting the resulting material with the amine
(4).
In the mixed acid anhydride process (a), the mixed acid anhydride
used can be obtained by an ordinary Schotten-Baumann reaction. The
anhydride is reacted with the amine (4) generally without being
isolated, whereby a compound of general formula (1a) can be
produced. The Schotten-Baumann reaction is conducted in the
presence of a basic compound. The basic compound is a compound
conventionally used in the Schotten-Baumann reaction and includes,
for example, organic bases such as triethylamine, trimethylamine,
pyridine, dimethylaniline, N-methylmorpholine,
4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN),
1,8-diazabicyclo-[5.4.0]undecene-7 (DBU),
1,4-diazabicyclo[2.2.2]octane (DABCO) and the like, and inorganic
bases such as sodium hydroxide, potassium hydroxide, potassium
carbonate, sodium carbonate, potassium hydrogen carbonate, sodium
hydrogen carbonate and the like. The reaction is conducted at
-20.degree. C. to 100.degree. C., preferably at
0.degree.-50.degree. C. for about 5 minutes to 10 hours, preferably
for about 5 minutes to 2 hours. The reaction of the resulting mixed
acid anhydride with the amine (4) is conducted at -20.degree. C. to
150.degree. C., preferably at 10.degree.-50.degree. C. for about 5
minutes to 10 hours, preferably for about 5 minutes to 5 hours. The
mixed acid anhydride process (a) is conducted in an appropriate
solvent or mixed solvent or in the absence of any solvent. The
solvent may be any solvent conventionally used in the mixed acid
anhydride process, and can be exemplified by halogenated
hydrocarbons such as dichloromethane, chloroform, dichloroethane
and the like; aromatic hydrocarbons such as benzene, toluene,
xylene and the like; ethers such as diethyl ether, dioxane,
diisopropyl ether, tetrahydrofuran, dimethoxyethane and the like;
esters such as methyl acetate, ethyl acetate and the like; and
aprotic polar solvents such as 1,1,3,3-tetramethylurea,
N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric
triamide and the like. The alkyl .alpha.-halocarboxylate used in
the mixed acid anhydride process (a) includes, for example, methyl
chloroformate, methyl bromoformate, ethyl chloroformate, ethyl
bromoformate and isobutyl chloroformate. The alkyl halocarboxylate
is used in an amount of generally at least 1 mole, preferably about
1-1.5 moles per mole of the amine (4). The carboxylic acid (3) is
used in an amount of generally at least 1 mole, preferably about
1-1.5 moles per mole of the amine (4).
The active ester process (b), when, for example, succinimidyl ester
is used, is conducted in the presence or absence of a basic
compound in an appropriate solvent which does not adversely affect
the reaction. To the reaction system may be added a condensation
agent such as dicyclohexylcarbodiimide, N,N-carbonyldiimidazole,
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide or the like. As the
basic compound, there can be used any basic compound used in the
Schotten-Baumann reaction. There can further be used alkali metal
carboxylates such as sodium acetate, sodium benzoate, sodium
formate, potassium acetate, lithium benzoate, cesium acetate and
the like; alkali metal halides such as potassium fluoride, cesium
fluoride and the like; and so forth. Specific examples of the
solvent are halogenated hydrocarbons such as dichloromethane,
chloroform, dichloroethane and the like; aromatic hydrocarbons such
as benzene, toluene, xylene and the like; ethers such as diethyl
ether, dioxane, tetrahydrofuran, dimethoxyethane and the like;
esters such as methyl acetate, ethyl acetate and the like; aprotic
polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide,
hexamethylphosphoric triamide and the like; and mixed solvents
thereof. The reaction is conducted at 0.degree.-200.degree. C.,
preferably at 10.degree.-150.degree. C. and is complete in 1 hour
to 3.5 days. With respect to the desirable proportions of the amine
(4) and the succinimidyl ester, the former is used in an amount of
generally at least 1 mole, preferably 1-2 moles per mole of the
latter.
A compound (1a) can also be obtained by reacting the carboxylic
acid (3) with the amine (4) in the presence of a phosphorus
compound as a condensation agent, such as
triphenylphosphine-2,2'-dipyridyl disulfide, diethyl
chlorophosphate, diphenylphosphinyl chloride, phenyl
N-phenylphospharamide chloridate (?), diethyl cyanophosphate,
bis(2-oxo-3-oxazolidinyl)phosphinic chloride or the like. As the
basic compound, there can be widely used known basic compounds, for
example, the basic compounds used in the Schotten-Baumann reaction,
sodium hydroxide and potassium hydroxide. As the solvent, there can
be cited, for example, the solvents used in the mixed acid
anhydride process (a), pyridine, acetone, acetonitrile and mixed
solvents of two or more of them. The reaction is conducted
generally at about -20.degree. C. to 150.degree. C. preferably at
about 0.degree.-100.degree. C. and is complete generally in about 5
minutes to 30 hours. With respect to the desirable amounts of the
condensation agent and the carboxylic acid (3), each of them is
used in an amount of at least 1 mole, preferably about 1-2 moles
per mole of the amine (4).
A compound (1a) can also be obtained by reacting the carboxylic
acid (3) with the amine (4) in the presence of a condensation
agent. The reaction is conducted in the presence or absence of a
catalyst in an appropriate solvent. The solvent can be exemplified
by halogenated hydrocarbons (e.g. dichloromethane, dichloroethane,
chloroform and carbon tetrachloride), acetonitrile and
N,N-dimethylformamide. The catalyst can be exemplified by organic
bases (e.g. 4-dimethylaminopyridine and 4-piperidinopyridine),
salts (e.g. pyridinium p-tosylate), camphorsulfonic acid and
mercury (II) oxide. As the condensation agent, there can be cited,
for example, acetylene compounds such as
trimethylsilylethoxyacetylene and the like. The condensation agent
is used in an amount of generally 1-10 moles, preferably 2-6 moles
per mole of the amine (4). The carboxylic acid (3) is used in an
amount of generally at least about 1 mole, preferably about 1-2
moles per mole of the amine (4). The reaction is conducted
generally at about 0.degree.-150.degree. C., preferably at about
room temperature to 100.degree. C. and is complete generally in
about 1-10 hours.
The compound (3) as a starting material can be produced, for
example, by the following reaction formulae. ##STR6## (wherein
R.sup.1 is the same as defined above; R.sup.10a and R.sup.10b are
each a lower alkyl group; R.sup.3a is a lower alkyl group or a
phenyl-lower alkyl group; R.sup.3b is a phenyl-lower alkyl group;
R.sup.4a is a tetrahydropyranyloxy group; R.sup.4b is a
phenyl-lower alkoxy group; X is a halogen atom; R.sup.11 is a
phenyl-lower alkyl group; and R.sup.12 is a lower alkyl group or a
phenyl-lower alkyl group).
The reaction of the compound (5) with the compound (6) is conducted
under the same conditions as in the reaction of the compound (3)
with the compound (4) in the Reaction formula-1. The reaction for
converting the compound (7) into a compound (7a) is conducted under
the same conditions as in the reaction for converting the compound
(20) into a compound (21) in the Reaction formula-6 to be described
later.
The reaction for converting the compound (7) or (7a) into a
compound (8) is conducted by first reducing the compound (7) or
(7a) in the presence of an acid in an appropriate solvent and then
subjecting the reduction product to cyclization. The solvent to be
used in the reducing reaction can be exemplified by water, acetic
acid, lower alcohols (e.g. methanol, ethanol and isopropanol) and
ethers (e.g. tetrahydrofuran, diethyl ether, dioxane and diglyme).
The acid can be exemplified by mineral acids (e.g. hydrochloric
acid) and organic acids (e.g. acetic acid). The reducing agent can
be exemplified by hydride reducing agents such as
borane-trimethylamine, sodium cyanoborohydride (?) and the like.
The amount of the hydride reducing agent used is at least 1 mole,
preferably 1-2 moles per mole of the compound (7) or (7a). The
reaction is conducted generally at 0.degree.-100.degree. C.,
preferably at about 0.degree.-70.degree. C. and is complete in
about 1-30 hours.
The subsequent cyclization is conducted in an appropriate solvent.
The solvent can be the same as used in the reaction of the
carboxylic acid (3) halide with the amine (4). The reaction is
conducted generally at room temperature to 200.degree. C.,
preferably at about 50-150.degree. C. and is complete in about
0.5-10 hours.
The reaction of the compound (8) with the compound (11) is
conducted in the presence of an acid in an appropriate solvent. The
solvent can be exemplified by halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride and the like;
ethers such as diethyl ether, tetrahydrofuran, dioxane, ethylene
glycol monomethyl ether and the like; aromatic hydrocarbons such as
benzene, toluene, xylene and the like; esters such as methyl
acetate, ethyl acetate and the like; ketones such as acetone,
methyl ethyl ketone and the like; polar solvents such as
acetonitrile, N,N -dimethylformamide, dimethyl sulfoxide,
hexamethylphosphoric triamide and the like; and mixed solvents
thereof. The acid can be exemplified by mineral acids (e.g.
hydrochloric acid, sulfuric acid and hydrobromic acid) and organic
acids (e.g. p-toluenesulfonic acid). The desirable amount of the
compound (11) used is generally at least 1 mole, preferably 1-2
moles per mole of the compound (8). The reaction is conducted
generally at 0-100.degree. C., preferably at about
0.degree.-70.degree. C. and is complete generally in about 0.5-10
hours.
The reaction of the compound (8) with the compound (9) is conducted
in the presence of a basic compound in an appropriate solvent. The
solvent can be exemplified by water; lower alcohols such as
methanol, ethanol, propanol and the like; ethers such as diethyl
ether, tetrahydrofuran, dioxane, ethylene glycol monomethyl ether
and the like; aromatic hydrocarbons such as benzene, toluene,
xylene and the like; ketones such as methyl acetate, ethyl acetate
and the like; ketones such as acetone, methyl ethyl ketone and the
like; polar solvents such as acetonitrile, N,N-dimethylformamide,
dimethyl sulfoxide, hexamethylphosphoric triamide and the like; and
mixed solvents thereof. The basic compound can be exemplified by
inorganic bases such as sodium hydroxide, potassium hydroxide,
sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
potassium hydrogen carbonate, sodium hydride and the like; alkali
metals such as sodium, potassium and the like; alkali metal
alcoholates such as sodium ethylate, sodium methylate and the like;
and organic bases such as triethylamine, pyridine,
N,N-dimethylaniline, N-methylmorpholine, 4-methylaminopyridine,
DBN, DBU, DABCO and the like. The compound (9) is used in an amount
of generally at least 1 mole, preferably 1-5 moles per mole of the
compound (8). The reaction is conducted generally at
0.degree.-150.degree. C., preferably at about 0.degree.-100.degree.
C. and is complete generally in about 0.5-20 hours.
The reaction of the compound (12) with the compound (13) is
conducted under the same conditions as in the reaction of the
compound (8) with the compound (9). ##STR7## (wherein R.sup.1,
R.sup.3, R.sup.4 and R.sup.10a are the same as defined above).
The reaction for converting the compound (15) into a compound (3)
is conducted by ordinary hydrolysis. Specifically, the hydrolysis
can be conducted in the presence of an acid such as mineral acid
(e.g. sulfuric acid, hydrochloric acid or nitric acid), organic
acid (e.g. acetic acid or aromatic sulfonic acid) or the like, or a
basic compound such as sodium carbonate, potassium carbonate,
sodium hydroxide, potassium hydroxide, barium hydroxide or the
like, in a solvent such as water, alcohol (e.g. methanol, ethanol
or isopropyl alcohol), ketone (e.g. acetone or methyl ethyl
ketone), ether (e.g. dioxane or ethylene glycol dimethyl ether),
acetic acid or mixed solvent thereof. The reaction proceeds
generally at about 0.degree.-200.degree. C., preferably at about
room temperature to 150.degree. C. and is complete generally in
about 0.5-15 hours.
A compound (1), a compound (1a) and a compound (10), wherein
R.sup.4 and/or R.sup.4b is a hydroxyl group, can be produced by
reducing a compound (1), a compound (1a) and a compound (10),
wherein R.sup.4 and/or R.sup.4b is a phenyl-lower alkoxy group.
This reduction can be conducted, for example, by subjecting the
material compound to catalytic hydrogenation in the presence of a
catalyst in an appropriate solvent. As the solvent, there can be
cited, for example, water; acetic acid; alcohols such as methanol,
ethanol, isopropanol and the like; hydrocarbons such as hexane,
cyclohexane and the like; ethers such as dioxane, tetrahydrofuran,
diethyl ether, ethylene glycol dimethyl ether and the like; esters
such as ethyl acetate, methyl acetate and the like; aprotic polar
solvents such as dimethylformamide and the like; and mixed solvents
thereof. As the catalyst, there can be cited, for example,
palladium, palladium black, palladiumcarbon, platinum, platinum
oxide, copper chromite and Raney nickel. The desirable amount of
the catalyst used is generally about 0.02-1 time by weight of the
starting material. The reaction temperature is generally about
-20.degree. C. to 100.degree. C., preferably about
0.degree.-80.degree. C.; the hydrogen pressure is generally 1-10
atm.; and the reaction is complete generally in about 0.5-20
hours.
A compound (1), a compound (1a) and a compound (10), wherein
R.sup.4 and/or R.sup.4b is a hydroxyl group, can be produced by
hydrolyzing a compound (1), a compound (1a) and a compound (10),
wherein R.sup.4 and/or R.sup.4b is a tetrahydropyranyloxy group.
This hydrolysis is conducted in the presence of an acid in an
appropriate solvent or without using any solvent. The solvent Can
be any solvent which does not adversely affect the reaction, and
there can be cited, for example, water; halogenated hydrocarbons
such as dichloromethane, chloroform and the like; lower alcohols
such as methanol, ethanol, isopropanol and the like; ketones such
as acetone, methyl ethyl ketone and the like; ethers such as
dioxane, tetrahydrofuran, ethylene glycol monomethyl ether,
ethylene glycol dimethyl ether and the like; fatty acids such as
formic acid, acetic acid and the like; and mixed solvents thereof.
As the acid, there can be cited, for example, mineral acids such as
hydrochloric acid, sulfuric acid, hydrobromic acid and the like;
and organic acids such as formic acid, trifluoroacetic acid, acetic
acid, aromatic sulfonic acid and the like. The amount of the acid
used has no particular restriction and can be appropriately
selected from a wide range, but desirably is equimolar to a large
excess relative to the raw material, preferably about 10-20 moles
per mole of the raw material. The reaction proceeds favorably
generally at about 0.degree.-200.degree. C. preferably at about
room temperature to 150.degree. C. and is complete generally in
about 5 minutes to 5 hours. ##STR8## (wherein R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are the same as defined above).
The reaction for converting the compound (16) into a compound (1)
is conducted under the same conditions as in the reaction of the
compound (3) with the compound (4) in the Reaction formula-1.
The compound (16) used as a starting material can be produced, for
example, by a process shown by the following reaction formula.
##STR9## (wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the
same as defined above; and R.sup.12 is a hydrogen atom, a lower
alkyl group or a lower alkyl group-containing silyl group).
The reaction of the compound (17) with the compound (18) is
conducted under the same conditions as in the reaction of the
compound (3) with the compound (4) in the Reaction formula-1.
The reaction for converting the compound (19) into a compound (16),
when R.sup.12 is a lower alkyl group, can be conducted under the
same conditions as in the reaction for converting the compound (15)
into a compound (3) in the reaction formula-3. Also, said reaction,
when R.sup.12 is a lower alkyl group-containing silyl group, can be
conducted under the same conditions as in the reaction for
converting a compound (1) wherein R.sup.4 is a tetrahydropyranyloxy
group, into a compound (1) wherein R.sup.4 is a hydroxyl group.
##STR10## (wherein R.sup.1, R.sup.4, R.sup.5, R.sup.6, R.sup.10a
and R.sup.10b are the same as defined above).
The reaction of the compound (5) with the compound (18) is
conducted under the same conditions as in the reaction of the
compound (3) with the compound (4) in the Reaction formula-1. The
reaction for converting the compound (20) into a compound (21) is
conducted under the same conditions as in the reaction for
converting the compound (15) into a compound (3) in the Reaction
formula-3. In this reaction, however, the amount of the basic
compound used is preferably 1 mole per mole of the compound (20).
The reaction of the compound (21) with the compound (4) is
conducted under the same conditions as in the reaction of the
compound (3) with the compound (4) in the Reaction formula-1.
##STR11## (wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.10a
are the same as defined above).
The reaction of the compound (17a) with the compound (6a) is
conducted under the same conditions as in the reaction of the
compound (5) with the compound (6) in the Reaction formula-2. The
reaction for converting the compound (22) into a compound (23) is
conducted under the same conditions as in the reaction for
converting the compound (15) into a compound (3) in the Reaction
formula-3. The reaction for converting the compound (22) into a
compound (1) and the reaction for converting the compound (23) into
a compound (1) are both conducted under the same conditions as in
the reaction for converting the compound (7) into a compound (8) in
the Reaction formula-2. ##STR12## (wherein R.sup.7, R.sup.8,
R.sup.9 and R.sup.10a are the same as defined above).
The reaction of the compound (24) with the compound (25) is
conducted under the same conditions as in the reaction of the
compound (3) with the compound (4) in the Reaction formula-1. The
reaction for converting the compound (26) into a compound (2) is
conducted under the same conditions as in the reaction for
converting the compound (7) into a compound (8) in the Reaction
formula-2. ##STR13## (wherein R.sup.7, R.sup.8, R.sup.9 and
R.sup.10a are the same as defined above).
The reaction of the compound (27) with the compound (25) is
conducted under the same conditions as in the reaction of the
compound (3) with the compound (4) in the Reaction formula-1. The
reaction for converting the compound (28) into a compound (29) is
conducted under the same conditions as in the reaction for
converting the compound (15) into a compound (3) in the Reaction
formula-3. The reaction for converting the compound (29) into a
compound (2) is conducted under the same conditions as in the
reaction of the compound (3) with the compound (4) in the Reaction
formula-1.
A compound (2) wherein R.sup.9 is a hydroxyl group, can be produced
by reducing a compound (2) wherein R.sup.9 is a phenyl-lower alkoxy
group. This reduction is conducted under the same conditions as in
the reduction of a compound (1) wherein R.sup.4 is a phenyl-lower
alkoxy group.
A compound (1) wherein R.sup.2, R.sup.5 or R.sup.6 is a
phenyl-lower alkyl group having at least one hydroxyl group as the
substituent(s) on the phenyl ring, can be produced by reducing a
compound (1) wherein R.sup.2, R.sup.5 or R.sup.6 is a phenyl-lower
alkyl group having at least one phenyl-lower alkoxy group as the
substituent(s) on the phenyl ring. A compound (2) wherein R.sup.7
is a phenyl-lower alkyl group having at least one hydroxyl group as
the substituent(s) on the phenyl ring, or is a hydroxyl
group-substituted lower alkyl group, can be produced by reducing a
compound (2) wherein R.sup.7 is a phenyl-lower alkyl group having
at least one phenyl-lower alkoxy group as the substituent(s) on-the
phenyl ring, or is a phenyl-lower alkoxy group-substituted lower
alkyl group. These reductions are conducted under the same
conditions as in the reduction of a compound (1) wherein R.sup.4 is
a phenyl-lower alkoxyl group.
Of the present compounds represented by general formulae (1) and
(2), those having a basic group can each be made into an acid
addition salt easily by being reacted with a pharmacologically
acceptable acid. As the acid, there can be cited, for example,
inorganic acids such as hydrochloric acid, sulfuric acid,
phosphoric acid, hydrobromic acid and the like; and organic acids
such as oxalic acid, acetic acid, succinic acid, malonic acid,
methanesulfonic acid, maleic acid, fumaric acid, malic acid,
tartaric acid, citric acid, benzoic acid and the like.
Of the present compounds represented by general formulae (1) and
(2), those having an acidic group can each be made into a salt
easily by being reacted with a pharmacologically acceptable basic
compound. As the basic compound, there can be cited, for example,
sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium
carbonate, potassium hydrogen carbonate and the like.
Each of the intended compounds obtained by the above reaction
formulas can be easily separated from the reaction system and
purified by ordinary means. The means for separation can be
exemplified by solvent extraction, dilution, recrystallization,
column chromatography and preparative thin-layer
chromatography.
Needless to say, the present compounds include optical isomers and
stereoisomers.
Each of the compounds of general formulae (1) and (2) is used
generally in the form of ordinary pharmaceutical preparation. The
pharmaceutical preparation is prepared by using diluents or
excipients ordinarily used, such as filler, bulking agent, binder,
humectant, disintegrator, surfactant, lubricant and the like. The
pharmaceutical preparation can be prepared in various forms
depending upon the purpose of remedy, and the typical forms include
tablets, pills, a powder, a solution, a suspension, an emulsion,
granules, capsules, suppositories, an injection (e.g. solution or
suspension), etc. In preparing tablets, there can be used various
carriers known in the art, exemplified by excipients such as
lactose, white sugar, sodium chloride, glucose, urea, starch,
calcium carbonate, kaolin, crystalline cellulose, silicic acid and
the like; binders such as water, ethanol, propanol, simple syrup,
glucose solution, starch solution, gelatin solution, carboxymethyl
cellulose, shellac, methyl cellulose, potassium phosphate,
polyvinylpyrrolidone and the like; disintegrators such as dry
starch, sodium alginate, powdered agar, powdered laminarin, sodium
hydrogen carbonate, calcium carbonate, polyoxyethylene
sorbitan-fatty acid esters, sodium lauryl sulfate, stearic acid
monoglyceride, starch, lactose and the like; disintegration
inhibitors such as white sugar, stearin, cacao butter, hydrogenated
oil and the like; absorption promoters such as quaternary ammonium
salts, sodium lauryl sulfate and the like; humectants such as
glycerine, starch and the like; adsorbents such as starch, lactose,
kaolin, bentonite, colloidal silicic acid and the like; and
lubricants such as refined talc, stearic acid salts, boric acid
powder, polyethylene glycol and the like.
The tablets can be prepared, as necessary, in the form of ordinary
coated tablets, such as sugar-coated tablets, gelatin-coated
tablets, enteric coated tablets or film-coated tablets, or in the
form of double-layered tablets or multi-layered tablets. In
preparing pills, there can be used various carriers known in the
art, exemplified by excipients such as glucose, lactose, starch,
cacao butter, hardened vegetable oils, kaolin, talc and the like;
binders such as powdered acacia, powdered tragacanth, gelatin,
ethanol and the like; and disintegrators such as laminarin, agar
and the like. In preparing suppositories, there can be used various
known carriers exemplified by a polyethylene glycol, cacao butter,
a higher alcohol, a higher alcohol ester, gelatin and a
semi-synthetic glyceride. In preparing an injection (solution,
emulsion or suspension), the solution and the suspension are
sterilized and are preferably made isotonic to the blood. In
preparing the solution, emulsion-or suspension, there can be used
all diluents conventionally used in the art, such as water, ethyl
alcohol, propylene glycol, ethoxylated isostearyl alcohol,
polyoxy-isostearyl alcohol and polyoxyethylene sorbitan-fatty acid
esters. In this case, the injection may contain sodium chloride,
glucose or glycerine in an amount sufficient to make the injection
isotonic, and may further contain a solubilizing agent, a buffer
solution, a soothing agent, etc. all ordinarily used. The
pharmaceutical preparation may furthermore contain, as necessary, a
coloring agent, a preservative, a perfume, a flavoring agent, a
sweetening agent and other drugs.
The amount of the compounds of general formulae (1) and (2) to be
contained in the pharmaceutical preparation is not particularly
restricted and can be appropriately selected from a wide range, but
the amount is generally 1-70% by weight, preferably 1-30% by weight
in the pharmaceutical preparation.
The method for administering the pharmaceutical preparation is not
particularly restricted. It is decided depending upon the form of
preparation, the age, distinction of sex and other conditions of
patient, the disease condition of patient, etc. For example,
tablets, pills, a solution, a suspension, an emulsion, granules or
capsules are administered orally. An injection is intravenously
administered singly or in admixture with an ordinary auxiliary
solution of glucose,amino acids or the like, or, as necessary, is
singly administered intramuscularly, intradermally, subcutaneously
or intraperitoneally. Suppositories are administered
intrarectally.
The dose of the pharmaceutical preparation is appropriately
selected depending upon the administration method, the age,
distinction of sex and other conditions of patient, the disease
condition of patient, etc., but the desirable dose is generally
about 0.5-30 mg per kg of body weight per day in terms of the
amount of the active ingredient, i.e. the compounds of general
formulae (1) and (2). The desirable content of the active
ingredient in each unit of administration form is about 10-1,000
mg.
The present invention is described more specifically below with
reference to Preparation Example, Reference Examples, Examples and
Pharmacological Tests.
______________________________________ Preparation Example 1
______________________________________
(3RS,6RS)-3-(3,5-di-tert-butyl-4-hydroxy- 150.0 g
benzyl)-1-hydroxy-6-isobutylpiperazine- 2,5-dione Citric acid 1.0 g
Lactose 33.5 g Dicalcium phosphate 70.0 g Pluronic F-68 (trademark
for a polyoxyalkylene 30.0 g glycol manufactured by BASF-Wyandott
Corp., N.J., U.S.A.) Sodium laurylsulfate 15.0 g
Polyvinylpyrrolidone 15.0 g Carbowax 1500 (trademark for a
polyethylene 4.5 g glycol manufactured by Union Carbide Corp.,
N.Y., U.S.A.) Carbowax 6000 (trademark for a polyethylene 45.0 g
glycol manufactured by Union Carbide Corp., N.Y., U.S.A.) Corn
starch 30.0 g Dried sodium laurylsulfate 3.0 g Dried magnesium
stearate 3.0 g Ethanol q.s.
______________________________________
The present compound, citric acid, lactose, dicalcium phosphate,
Pluronic F-68 and sodium laurylsulfate were mixed.
The mixture was sieved through a screen of No. 60, and the sieved
material was subjected to wet granulation with an ethanolic
solution containing polyvinylpyrrolidone, Carbowax 1500 and
Carbowax 6000. As necessary, ethanol was added and the resulting
material was made into a paste-like lump. Corn starch was added to
this lump and mixing was continued until granules of uniform
particle size were formed. The granules were sieved through a
screen of No. 10, and the sieved granules were placed on a tray and
dried in an oven at 100.degree. C. for 12-14 hours. The dried
granules were sieved through a screen of No. 16, and to the sieved
granules were added dried sodium laurylsulfate and dried magnesium
stearate. The whole mixture was mixed well and was compressed into
a desired form by using a tablet machine, to obtain tablets each to
be used as the core portion of a coated tablet.
The core portions were treated with a varnish, and the treated
surfaces thereof were coated with talc for preventing the surfaces
from moisture adsorption. The resulting surfaces of core portions
were further coated with a primary coating and further coated with
a varnish a plurality of times necessary for oral administration.
In order to obtain final tablets having a completely spherical
shape with a smooth surface, the coated tablets were further coated
with a primary coating and a smoothening agent. The resulting
tablets were coated with a coloring agent until the surfaces had a
desired color. After the coated tablets were dried, the surfaces
thereof were polished to prepare tablets having a uniform
gloss.
REFERENCE EXAMPLE 1
240 ml of 7N hydrochloric acid (an ethanolic solution) was dropwise
added to 240 ml of an ethanolic solution containing 18.46 g of
diethyl N-(2-hydroxyimino-4-methylpentanoyl)aminomalonate and 5.49
g of borane-trimethylamine, with ice-cooling. The mixture was
stirred at room temperature for 15 hours. The reaction mixture was
subjected to vacuum distillation at room temperature to remove the
solvent. The residue was dissolved in dichloromethane. The
resulting solution was washed with an aqueous solution saturated
with sodium chloride and an aqueous solution saturated with sodium
hydrogen carbonate in this order, then dried with anhydrous
magnesium sulfate, and was subjected to distillation to remove the
solvent. The resulting yellow oily substance was dissolved in 120
ml of toluene. The solution was refluxed for 1 hour and then
subjected to distillation to remove the solvent. 19.02 g of the
resulting orange oily substance was purified by silica gel column
chromatography (eluant: dichloromethane/methanol =30/1) to obtain
2.94 g of 3-ethoxycarbonyl-1-hydroxy-6-isobutylpiperazine-2,5-dione
as an orange oily substance.
.sup.1 H-NMR (DMSO-d.sub.6, 250 MHz) .delta. ppm: 0.87 (3H, d,
J=6.5 Hz), 0.88 (3H, d, J=6.5 Hz), 1.20 (1.4H, d, J=7 Hz), 1.21
(0.6H, d, J=7 Hz), 1.60-1.85 (2H, m), 1.85-2.05 (1H, m), 4.01 (1H,
t, J=6.5 Hz), 4.16 (2H, q, J=7 Hz), 4.65 (0.7H, d, J=3.5 Hz), 4.82
(0.3H, s), 8.56 (0.7H, d, J=8 Hz), 8.60 (0.3H, brs), 10.30 (1H,
brs)
REFERENCE EXAMPLE 2
7.60 g of potassium carbonate and 6.3 ml of benzyl chloride were
added to 100 ml of a solution of 9.57 g of
3-ethoxycarbonyl-1-hydroxy-6-isobutylpiperazine-2,5-dione in
anhydrous N,N-dimethylformamide, on ice-cooling. The mixture was
stirred at room temperature for 16 hours. The reaction mixture was
diluted with 450 ml of ethyl acetate, then washed three times with
an aqueous solution saturated with sodium chloride, and dried with
anhydrous magnesium sulfate. The resulting solution was subjected
to distillation to remove the solvent. The residue was allowed to
stand. The resulting crystals were collected by filtration and
washed with methanol to obtain 4.51 g of
(3RS,6SR)-3-benzyl-1-benzyloxy-3-ethoxycarbonyl-6-isobutylpiperazine-2,5-d
ione as colorless columnar crystals.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.80 (3H, d, J=6.5
Hz), 0.81 (3H, d, J=6.5 Hz), 1.32 (3H, t, J==7 Hz), 1.60-1.80 (2H,
m), 1.80 2.00 (1H, m), 3.32, 3.65 (each 1H, d, J=14 Hz), 3.59 (1H,
dd, J=6 Hz, 7 Hz), 4.29 (2H, q, J=7 Hz), 4.51, 4.80 (each 1H, d,
J=10.5 Hz), 6.55-6.95 (1H, br), 7.06 (2H, d, J=7 Hz), 7.20 7.50
(8H, m)
REFERENCE EXAMPLE 3
5.3 ml of 1N sodium hydroxide was added to 25 ml of a suspension of
2.32 g of
(3RS,6SR)-3-benzyl-1-benzyloxy-3-ethoxycarbonyl-6-isobutylpiperazine-2,5-d
ione in ethanol. The mixture was stirred at room temperature for
1.5 hours. The reaction mixture was adjusted to pH 3 with 1N
hydrochloric acid. Thereto were added 80 ml of ethyl acetate and 80
ml of water to conduct distribution. The organic layer was dried
with anhydrous magnesium sulfate and then subjected to vacuum
distillation to remove the solvent at room temperature to obtain
2.17 g of
(3RS,6SR)-3-benzyl-1-benzyloxy-3-carboxy-6-isobutylpiperazine-2,5-dione
as a light yellow solid.
.sup.1 H-NMR (DMSO-d.sub.6, 250 MHz) .delta. ppm: 0.70 (3H, d,
J=6.5 Hz), 0.71 (3H, d, J-6.5 Hz), 1.50-1.65 (2H, m), 1.65-1.85
(1H, m), 3.07, 3.53 (each 1H, d, J=13.5 Hz), 3.43 (1H, t, J-6 Hz),
4.34, 4.58 (each 1H, d, J=10.5 Hz), 6.94 (2H, d, J=6.5 Hz),
7.10-7.45 (9H, m), 8.87 (1H, brs)
By using suitable starting materials and by employing the same
manner as in Reference Example 3, there was obtained the following
compound.
(3RS,6SR)-3-Carboxy-6-isobutyl-3-methyl-1-(2-tetrahydropyranyloxy)piperazi
ne-2,5-dione Brown oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.96 (3H, d, J=6
Hz), 0.97 (3H, d, J=6 Hz), 1.45-2.00 (9H, m), 1.78 (1.5H, s), 1.83
(1.5H, s), 3.55-3.75 (1H, m), 3.80-3.95 (1H, m), 4.50-4.70 (1H, m),
5.05-5.20 (1H, m), 6.71 (2H, brs)
REFERENCE EXAMPLE 4
0.45 g of p, toluenesulfonic acid hydrate was added to 60 ml of a
solution of 6.15 g of
3-ethoxycarbonyl-1-hydroxy-6-isobutylpiperazine-2,5-dione and 4 ml
of 3,4-dihydro-2H-pyran in anhydrous dichloromethane. The mixture
was stirred at room temperature for 4 hours. The reaction mixture
was washed with an aqueous solution saturated with sodium hydrogen
carbonate and then dried with anhydrous magnesium sulfate. The
resulting mixture was subjected to distillation to remove the
solvent to obtain 9.67 g of
3-ethoxycarbonyl-6-isobutyl-1-(2-tetrahydropyranyloxy)piperazine-2,5-dione
as an orange oily substance.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.97 (3H, t, J=7
Hz), 0.98 (3H, t, J=7 Hz), 1.33 (3H, t, J=7 Hz), 1.45-1.95 (9H, m),
3.55-3.70 (1H, m), 3.80-3.95 (1H, m), 4.20-4.40 (2H, m), 4.5-4.60
(1H, m), 4.65-4.80 (1H, m), 5.15-5.22 (1H, m), 6.72 (1H, brs)
REFERENCE EXAMPLE 5
1.04 g of 60% sodium hydride was added to 100 ml of 9.67 g of
3-ethoxycarbonyl-6-isobutyl-1-(2-tetrahydropyranyloxy)piperazine-2,5-dione
in anhydrous N,N-dimethylformamide, on ice cooling, and the mixture
was stirred for 10 minutes. Thereto was added 3.5 ml of methyl
iodide. The mixture was stirred at room temperature for 5 hours.
The reaction mixture was ice-cooled and poured into an aqueous
solution saturated with ammonium chloride. The mixture was
extracted with ethyl acetate. The extract was washed three times
with an aqueous solution saturated with sodium chloride, dried with
anhydrous magnesium sulfate, and subjected to distillation to
remove the solvent to obtain 8.53 g of
(3RS,6SR)-3-ethoxycarbonyl-6-isobutyl-3-methyl-1-(2-tetrahydropyranyloxy)p
iperazine-2,5-dione as a brown oily substance.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.98 (3H, d, J=6.5
Hz), 0.99 (3H, d, J=6.5 Hz), 1.26 (1.5H, t, J=7 Hz), 1.31 (1.5H, t,
J=7 Hz), 1.45-1.90 (9H, m), 1.71 (1.5H, s), 1.75 (1.5H, s),
3.60-3.70 (1H, m), 3.85-3.95 (1H, m), 4.25 (2H, q, J=7 Hz),
4.50-4.60 (1H, m), 5.00-5.20 (1H, m)
REFERENCE EXAMPLE 6
14.86 g of dicyclohexylcarbodiimide was added to 200 ml of a
solution of 17.07 g of N-benzyloxyleucine and 9.09 g of
N-hydroxysuccinimide in anhydrous dioxane. The mixture was stirred
at room temperature for 2 hours. The resulting insoluble materials
were removed by filtration. To the filtrate was added 28.94 g of
ethyl (3', 5'-di-tert-butyl)tyrosinate The mixture was stirred at
room temperature for 12 hours. The reaction mixture was diluted
with 1,000 ml of ethyl acetate. The resulting solution was washed
with 1N hydrochloric acid, an aqueous solution saturated with
sodium hydrogen carbonate and an aqueous solution saturated with
sodium chloride in this order, then dried with anhydrous magnesium
sulfate, and subjected to distillation to remove the solvent. The
residue was purified by silica gel column chromatography (eluant:
ethyl acetate/n-hexane =1/6 - 1/4) to obtain 34.63 g of ethyl
N-(N-benzyloxyleucyl)-(3',5'-di-tert-butyl)tyrosinate as a brown
oily substance.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.75-0.95 (6H, m),
1.22 (1.6H, t, J=7 Hz), 1.26 (0.4H, t, J=7 Hz), 1.30-1.50 (1H, m),
1.39 (14.4H, s), 1.40 (3.6H, s), 1.50-1.70 (1H, m), 3.01, 3.10
(each 1H, dd, J=6 Hz, 14 Hz), 3.35-3.55 (1H, m), 4.05-4.25 (2H, m),
4.43, 4.53 (each 0.2H, d, J=12 Hz), 4.61, 4.71 (each 0.8H, d, J=12
Hz), 4.75-4.95 91H, m), 5.10 (0.2H, s), 5.12 (0.8, s), 5.59 (0.8H,
d, J=4.5 Hz), 5.67 (0.2H, d, J=6 Hz), 6.74 (0.2H, d, J=8.5 Hz),
6.91 (1.6H, s), 6.92 (0.4H, s), 7.02 (0.8H, d, J=8.5 Hz), 7.20-7.45
(5H, m)
REFERENCE EXAMPLE 7
By using suitable starting materials and by employing the same
manner as in REFERENCE EXAMPLE 6, there were obtained the following
compounds.
Ethyl N-(N-benzyloxyleucyl)-(3',5'-dimethoxy)tyrosinate Colorless
oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.85, 0.87 (each
2.4H, d, J=6.5 Hz), 0.86, 0.91 (each 0.6H, d, J=6.5 Hz), 1.15-1.50
(5H, m), 1.50-1.65 (1H, m), 3.00-3.20 (2H, m), 3.49 (1H, dd, J=5.5
Hz, J=8 Hz), 3.82 (6H, s), 4.10-4.30 (2H, m), 4.46, 4.56 (each
0.2H, d, J=12 Hz), 4.63, 4.72 (each 0.8H, d, J=l 2 Hz), 4.91 (1H,
dt, J=6 Hz, J=98 Hz), 5.46 (1H, brs), 6.35 (1.6H, s), 6.38 (0.4H,
s), 6.92 (0.2H, d, J=8 Hz), 7.02 (0.8H, d, J=8 Hz), 7.15-7.50 (5H,
m)
Ethyl N-(N-benzyloxyleucyl)-(3',5'-dimethyl)tyrosinate Yellow oily
substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.85, 0.87 (each
0.6H, d, J=6 Hz), 0.86, 0.89 (each 2.4H, d, J=7 Hz), 1.27 (3H, t,
J=7 Hz), 1.20-1.45 (2H, m), 1.55-1.70 (1H, m), 2.15 (1.2H, s), 2.17
(4.8H, s), 2.90-3.15 (2H, m), 3.40-3.55 (1H, m), 4.10 (2H, q, J=7
Hz), 4.64, 4.74 (each 1H, d, J=12 Hz), 4.86 (1H, dt, J=5.5 Hz, J=8
Hz), 5.66 (1H, brs), 6.73 (1.6H, s), 6.76 (0.4H, s), 6.81 (0.2H, d,
J=9.5 Hz), 7.00 (0.8H, d, J=8 Hz), 7.20-7.45 (5H, m)
REFERENCE EXAMPLE 8
13.2 ml of triethylamine and 6 ml of trimethylsilyl chloride were
added to 150 ml of a suspension of 11.78 g of
(2',4'-dimethoxy)phenylalanine hydrochloride in anhydrous
dichloromethane, in a nitrogen atmosphere. The mixture was refluxed
for 1.5 hours. Separately, 9.28 g of dicyclohexylcarbodiimide was
added to 100 ml of a solution of 10.68 g of N-benzyloxyleucine and
5.18 g of N-hydroxysuccinimide in anhydrous dioxane. The mixture
was stirred at room temperature for 2 hours. The resulting
insoluble materials were removed by filtration. The filtrate was
added to the above reaction mixture after refluxing, at room
temperature. The resulting mixture was stirred for 12 hours. The
reaction mixture was diluted with 1,200 ml of ethyl acetate. The
resulting solution was washed with 1N hydrochloric acid, an aqueous
solution saturated with sodium chloride, an aqueous solution
saturated with sodium hydrogen carbonate and an aqueous solution
saturated with sodium chloride in this order, then dried with
anhydrous magnesium sulfate, and subjected to vacuum distillation
to remove the solvent to obtain 17.40 g of
N-(N-benzyloxyleucyl)-(2',4'-dimethoxy)phenylalanine as a light
brown vitreous substance.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.82, 0.85 (each
1.5H, d, J=6.5 Hz), 0.87, 0.92 (each 1.5H, d, J=6.5 Hz), 1.05-1.30
(2H, m), 1.45-1.60 (1H, m), 3.05-3.02 (1H, m), 3.35-3.55 (1H, m),
3.74 (3H, s), 3.75 (3H, s), 3.90-4.05 (0.5H, m), 4.10-4.25 (0.5H,
m), 4.50-4.80 (3H, m), 6.30-6.50 (2H, m), 7.01 (1H, d, J=8 Hz),
7.15-7.40 (5H, m)
By using suitable starting materials and by employing the same
manner as in Reference Example 8, there was obtained the compound
of Reference Example 9 described below.
REFERENCE EXAMPLE 9
64 ml of a 2N aqueous sodium hydroxide solution was added to a
solution of 34.63 g of ethyl
N-(N-benzyloxyleucyl)-(3',5'-di-tert-butyl)tyrosinate in ethanol.
The mixture was stirred at room temperature for 1.5 hours. The
reaction mixture was adjusted to pH 1 with concentrated
hydrochloric acid. Thereto was added 500 ml of water. The mixture
was extracted with ethyl acetate twice. The extract was washed with
an aqueous solution saturated with sodium chloride, then dried with
anhydrous magnesium sulfate, and subjected to vacuum distillation
to remove the solvent to obtain 32.83 g of
N-(N-benzyloxyleucyl)-(3',5'-di-tert-butyl)tyrosine as a brown oily
substance.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.82 (3H, d, J=6.5
Hz), 0.84 (3H, d, J=6.5 Hz), 1.10-1.37 (2H, m), 1.39 (18H, s),
1.45-1.65 (1H, m), 2.99 (0.43H, dd, J=7 Hz, J=14 Hz), 3.16 (0.43H,
dd, J=5.5 Hz, J=14 Hz), 3.04-3.28 (0.15H, m), 3.42 (0.15H, dd, J=6
Hz, J=8 Hz), 3.51 (0.85H, dd, J=5 Hz, J=9 Hz), 4.35, 4.42 (each
0.15H, d, J=12 Hz), 4.53, 4.60 (each 0.85H, d, J=12 Hz),
4.70-4.90(1H, m), 5.13 brs), 6.94 (2H, s), 6.96 (1H, d, J=9 Hz),
7.15-7.45 (5H, m)
By using suitable starting materials and by employing the same
manner as in Reference Example 9, there was obtained the compound
of Reference Example 8.
REFERENCE EXAMPLE 10
By using suitable starting materials and by employing the same
manners as in Reference Examples 8 and 9, there were obtained the
following compounds.
N-(N-Benzyloxyleucyl)-(3',5'-dimethoxy)tyrosine Colorless oily
substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.83 (3H, d, J=6
Hz), 0.85 (3H, d, J=6 Hz), 1.15-1.45 (2H, m), 1.45-1.65 (1H, m),
3.04 (1H, dd, J=6.5 Hz, J=14 Hz), 3.16 (1H, dd, J=5.5 Hz, J=14 Hz),
3.52 (1H, dd, J=5.5 Hz, J=8.5 Hz), 3.79 (3H, s), 3.80 (3H, s),
4.40, 4.48 (each 0.2H, d, J=12 Hz), 4.75-5.00 (1H, m), 6.39 (1.6H,
s), 6.42 (0.4H, s), 6.10-6.90 (2H, br), 6.98 (0.2H, d, J=7 Hz),
7.08 (0.8, d, J=7.5 Hz), 7.15-7.40 (5H, m)
N-(N-Benzyloxyleucyl)-(3',5'-dimethyl)tyrosine White solid
.sup.1 H-NMR (DMSO-d.sub.6, 250 MHz) .delta. ppm: 0.80 (3H, d,
J=6.5 Hz), 0.86 (3H, d, J=6.5 Hz), 1.30-1.45 (2H, m), 1.50-1.70
(1H, m), 2.03 (6H, s), 2.77 (1H, dd, J-7.5 Hz, J=14 Hz), 2.87 (1H,
dd, J=5.5 Hz, J=14 Hz), 3.83 (1H, t, J=8 Hz), 4.44 (1H, dd, J=5 Hz,
J=8 Hz), 4.80 (2H, s), 76.70 (2H, s), 7.20-7.40 (5H, m), 8.45 (1H,
brs)
(N-Benzyloxy-DL-tryptophyl)-L-serine Brown foam-like substance
.sup.1 H-NMR (DMSO-d.sub.6, 250 MHz) .delta. ppm: 2.80-3.00 (1H,
m), 3.00-3.15 (1H, m), 3.45-3.65 (1H, m), 3.65-3.85 (1H, m),
3.90-4.05 (1H, m), 4.30-4.45 (1H, m), 4.67, 4.73 (1H, d, J=11 Hz),
6.97 (1H, t, J=7.5 Hz), 7.07 (1H, t, J=7 Hz), 7.17 (1H, d, J=7 Hz),
7.29 (5H, s), 7.34 (1H, d, J=8 Hz), 7.55 (1H, d, J=8 Hz), 8.21 (1H,
d, J=8 Hz), 10.87 (1H, brs)
REFERENCE EXAMPLE 11
26.82 g of dicyclohexylcarbodiimide was added to one liter of a
solution of 34.47 g of methyl (3',4',5'-trimethoxy)phenylalaninate,
18.87 of 2-hydroxyimino-4-methylpentanoic acid and 14.96 g of
N-hydroxysuccinimide in anhydrous dioxane. The mixture was stirred
at room temperature for 18 hours. The reaction mixture was filtered
and the filtrate was subjected to distillation to remove the
solvent. The residue was purified by silica gel column
chromatography (eluant: ethyl acetate/n-hexane=1/2) to obtain 42.70
g of methyl
N-(2-hydroxyimino-4-methylpentanoyl)-(3',4',5'-trimethoxy)phenylalaninate.
White powder
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.90 (6H, d, J=6.5
Hz), 1.90-2.11 (1H, m), 2.52 (2H, d, J=7.5 Hz), 3.02-3.18 (2H, m),
3.74 (3H, s), 3.81 (6H, s), 3.82 (3H, s), 4.91 (1H, dt, J=6 Hz,
J=8.5 Hz), 6.32 (2H, s), 7.17 (1H, d, J=8.5 Hz), 7.83 (1H, brs)
REFERENCE EXAMPLE 12
By using suitable starting materials and by employing the same
manner as in Reference Examples 11, there were obtained the
following compounds.
Ethyl
N-(2-hydroxyimino-4-methylpentanoyl)-(3',5'-di-tert-butyl)tyrosinate.
White powder
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.90 (6H, d, J=6.5
Hz), 1.21 (3H, t, J=7 Hz), 1.28 (18H, s), 1.80-2.15 (1H, m), 2.52
(2H, d, J=7.5 Hz), 3.00 (1H, dd, J=6 Hz, J=14 Hz), 3.07 (1H, dd,
J=6 Hz, J=14 Hz), 4.00-4.23 (2H, m), 4.82 (1H, dt, J=6 Hz, J=8 Hz),
5.10 (1H, s), 6.89 (2H, s), 7.15 (1H, brd, J=8.5 Hz), 7.56 (1H,
brs) Methyl N-
(2-hydroxyimino-4-methylpentanoyl)-L-phenylalaninate
Colorless needle-like crystals
Melting point: 71.degree.-73.degree. C.
Methyl
N-(2-hydroxyimino-4-methylpentanoyl)-O-benzyl-L-tyrosinate
Colorless needle-like crystals
Melting point: 108.degree.-110.degree. C.
Ethyl
N-(2-hydroxyimino-4-methylpentanoyl)-(3',5'-dichloro)-L-tyrosinate
White solid
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.91 (6H, d, J=6.5
Hz), 1.27 (3H, t, J=7 Hz), 1.90-2.10 (1H, m), 2.52 (2H, d, J=7.5
Hz), 2.98 91H, dd, J=6 Hz, J=14 Hz), 3.08 (1H, dd, J=6 Hz, J=14
Hz), 4.20, 4.21 (each 1H, q, J=7 Hz), 4.81 (1H, dt, J=6 Hz, J=8
Hz), 5.86 (1H, s), 7.03 (2H, s), 7.26 (1H, d, J=8 Hz), 8.24 (1H,
brs)
Methyl N.sup.in
-Benzyl-N-(2-hydroxyimino-4-methylpentanoyl)-L-histidinate
White solid
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.86 (3H, d, J=6.5
Hz), 0.88 (3H, d, J=6.5 Hz), 1.88-2.10 (1H, m), 2.49 (2H, d, J=7.5
Hz), 3.09 (1H, dd, J=7.5 Hz, J=14.5 Hz), 3.17 (1H, dd, J=6 Hz,
J=14.5 Hz), 3.62 (3H, s), 4.87 (1H, dt, J=7 Hz, J=8 Hz), 5.03 (2H,
s), 6.77 (1H, s), 7.10-7.23 (2H, m), 7.30-7.46 (3H, m), 7.44 (1H,
s), 8.16 (1H, d, J=8.5 Hz), 23.66 (1H, brs)
REFERENCE EXAMPLE 13
180 ml of 1N sodium hydroxide was added to 500 ml of a solution of
31.98 g of methyl N-(2-hydroxy-
imino-4-methylpentanoyl)-(3',4',5'-trimethoxy)phenylalaninate in
ethanol. The mixture was stirred at room temperature for 13 hours.
The reaction mixture was subjected to distillation to remove
ethanol. The residue was made acidic with hydrochloric acid and
then extracted with ethyl acetate. The extract was washed with an
aqueous solution saturated with sodium chloride, then dried with
anhydrous magnesium sulfate, and subjected to distillation to
remove the solvent to obtain 30.93 g of
N-(2-hydroxyimino-4-methylpentanoyl)(3',4',5'-trimethoxy)phenylalanine.
White powder
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.85 (3H, d, J=6.5
Hz), 0.8 (3H, d, J=6.5 Hz), 1.88-2.07 (1H, m), 2.48 (1H, dd, J=12.5
Hz, J=19.5 Hz), 2.50 (1H, dd, J=12.5 Hz, J=19.5 Hz), 3.05 (1H, dd,
J=7.5 Hz, J=14 Hz), 3.20 (1H, dd, J=5 Hz, J=14 Hz), 3.77 (6H, s),
3.80 (3H, s), 4.92 (1H, dt, J=6 Hz, J=8.5 Hz), 6.38 (2H, s), 7.28
(1H, d, J=8.5 Hz)
REFERENCE EXAMPLE 14
The following compounds were obtained by using suitable starting
materials and by employing the same manner as in Reference Example
13.
N-(2-Hydroxyimino-4-methylpentanoyl)-L-phenylalanine
White powder
Melting point: 120.degree.-122.degree. C.
N-(2-Hydroxyimino-4-methylpentanoyl)-o-benzyl-L-tyrosine
Colorless needle-like crystals
Melting point: 147.degree.-148.degree. C.
N.sup.in
-Benzyl-N-(2-hydroxyimino-4-methylpentanoyl)-L-histidine
White powder
.sup.1 H-NMR (DMSO-d.sub.6, 250 MHz) .delta. ppm: 0.82 (6H, d,
J=6.5 Hz), 1.80-2.00 (1H, m), 2.36 (2H, d, J=7.5 Hz), 2.94 (1H, dd,
J=5 Hz, J=15 Hz), 3.03 (11H, dd, J=7 Hz, J=15 Hz), 4.56 (1H, dt,
J=6 Hz, J=8 Hz), 5.19 (2H, s), 7.03 (1H, s), 7.20-7.30 (2H, m),
7.30-7.45 (3H, m), 7.95 (1H, s), 8.22 (1H, d, J=8 Hz), 11.81 (1H,
s)
REFERENCE EXAMPLE 15
22.90 g of dicyclohexylcarbodiimide was added to 300 ml of a
solution of 26.39 g of N-benzyloxyleucine and 13.35 g of
N-hydroxysuccinimide in anhydrous dioxane. The mixture was stirred
at room temperature for 2 hours. The reaction mixture was filtered
to remove the insoluble materials, whereby a colorless solution was
obtained. Separately, 20 ml of triethylamine was added to 300 ml of
a suspension of 28.57 g of diethyl aminomalonate hydrochloride in
anhydrous dioxane. To the mixture was applied an ultrasonic wave
for 1 hour. Thereto was added the above colorless solution. The
mixture was stirred at room temperature for 16 hours and then at a
bath temperature of 100.degree. C. for 3.5 hours. The reaction
mixture was subjected to distillation to remove the solvent. The
residue was dissolved in 1,000 ml of ethyl acetate. The solution
was washed with 1N hydrochloric acid, an aqueous solution saturated
with sodium hydrogen carbonate and an aqueous solution saturated
with sodium chloride in this order, then dried with anhydrous
magnesium sulfate, and subjected to distillation to remove the
solvent to obtain 39.22 g of diethyl
N-(N-benzyloxyleucyl)aminomalonate as a yellow oily substance.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.88 (3H, d, J=6.5
Hz), 0.91 (3H, d, J=6.5 Hz), 1.30 (6H, t, J=7 Hz), 1.35-1.55 (2H,
m), 1.60-1.80 (1H, m), 3.57 (1H, dt, J=5.5 Hz, J=8.5 Hz), 4.20-4.40
(4H, m), 4.73, 4.82 (each 1H, d, J=12 Hz), 5.21 (1H, d, J=7 Hz),
5.69 (1H, d, J=5 Hz), 7.25-7.40 (5H, m), 7.52 (1H, d, J=7 Hz)
REFERENCE EXAMPLE 16
90 ml of 1N sodium hydroxide was added to 180 ml of a solution of
35.28 g of diethyl N-(N-benzyloxyleucyl)aminomalonate in ethanol,
on ice-cooling. The mixture was diluted with 600 ml of water on
ice-cooling and the resulting mixture was washed with diethyl ether
(500 ml.times.2). The aqueous layer was adjusted to pH 1 with
concentrated hydrochloric acid and extracted with ethyl acetate
(500 ml.times.2)on ice-cooling. The extract was washed twice with
an aqueous solution saturated with sodium chloride, then dried with
anhydrous magnesium sulfate, and subjected to distillation to
remove the solvent to obtain 28.72 g of ethyl
N-(N-benzyloxyleucyl)aminomalonate as a white solid.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.89 (3H, d, J=6
Hz), 0.91 (3H, d, J=6 Hz), 1.32 (3H, t, J=7 Hz), 1.30-1.55 (2H, m),
1.55-1.80 (1H, m), 3.61 (1H, dd, J=6 Hz, J=8.5 Hz), 4.31 (2H, q,
J=7 Hz), 4.77, 4.80 (each lit, d, J=12 Hz), 5.17 (0.5H, d, J=6.5
Hz), 5.19 (0.5H, d, J=5 Hz), 5.25 (2H, brs), 7.25-7.45 (5H, m),
7.71 (1H, d, J=6.5 Hz)
REFERENCE EXAMPLE 17
1.03 g of dicyclohexylcarbodiimide was added to 30 ml of a solution
of 1.83 g of ethyl N-(N-benzyloxyleucyl)aminomalonate, 0.58 g of
N-hydroxysuccinimide and 1.3 ml of (3-methoxybenzyl)amine in
anhydrous dioxane. The mixture was stirred at room temperature for
2 hours. The reaction mixture was filtered to remove-the insoluble
materials. The filtrate was diluted with 100 ml of ethyl acetate.
The resulting solution was washed with 1N hydrochloric acid, an
aqueous solution saturated with sodium hydrogen carbonate and an
aqueous solution saturated with sodium chloride in this order, then
dried with anhydrous magnesium sulfate, and subjected to
distillation to remove the solvent. 1.49 g of the resulting yellow
oily substance was purified by silica gel column chromatography
(eluant: ethyl acetate/n-hexane=1/2)to obtain 0.96 g of ethyl
N-(N-benzyloxyleucyl)-.alpha.-[N-(3-methoxybenzyl)carbamoyl]glycinate
as a colorless oily substance.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.85 (1.5H, d,
J=6.5 Hz), 0.87 (1.5H, d, J=6.5 Hz), 0.88 (1.5H, d, J=6.5 Hz), 0.90
(1.5H, d, J=6.5 Hz), 1.26 (1.5H, t, J=7 Hz), 1.27 (1.5H, t, J=7
Hz), 1.30-1.55 (2H, m), 1.55-1.75 (1H, m), 3.56 (1H, dt, J=6 Hz,
J=8 Hz), 3.78 (3H, s), 4.15-4.35 (2H, m), 4.35-4.55 (2H, m), 4.70,
4.76 (each 0.5H, d, J=12 Hz), 4.72, 4.78 (each 0.5H, d, J=12 Hz),
5.13 (0.5H, d, J=7 Hz), 5.14 (0.5H, d, J=7 Hz), 6.75-7.00 (4H, m),
7.21 (1H, d, J=7.5 Hz), 7.30-7.50 (5H, m), 7.62 (0.5H, d, J=7 Hz),
7.75 (0.5H, d, J=7 Hz)
REFERENCE EXAMPLE 18
The following compounds were obtained by using suitable starting
materials and by employing the same manner as in Reference Example
17.
Ethyl
N-(N-benzyloxyleucyl)-.alpha.-[N-(2,4-dimethoxybenzyl)carbamoyl]glycinate
White solid
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.85 (1.5H, d,
J=6.5 Hz), 0.86 (1.5H, d, J=6.5 Hz), 0.88 (1.5H, d, J=6.5 Hz), 0.89
(1.5H, d, J=6.5 Hz), 1.21 (1.5H, t, J=7 Hz), 1.22 (1.5H, t, J=7
Hz), 1.30-1.55 (2H, m), 1.55-1.80 (1H, m), 3.54 (1H, dt, J=6 Hz,
J=8 Hz), 3.79 (3H, s), 3.83 (3H, s), 4.20 (1H, q, J=7 Hz), 4.22
(1H, q, J=7 Hz), 4.38 (1H, d, J=6 Hz), 4.40 (1H, d, J=6 Hz), 4.70,
4.77 (each 0.5H, d, J=12 Hz), 4.71, 4.78 (each 0.5H, d, J=12 Hz),
5.04 (0.5H, d, J=7 Hz), 5.06 (0.5H, d, J=7 Hz), 6.41 (0.5H, dd,
J=2.5 Hz, J=8 Hz), 6.42 (0.5H, dd, J=2.5 Hz, J=8 Hz), 6.45 (1H, d,
J=2.5 Hz), 6.88 (1H, brt, J=8 Hz), 7.14 (1H, d, J=8 Hz), 7.25-7.45
(5H, m), 7.59 (0.5H, d, J=7 Hz), 7.72 (0.5H, d, J=7 Hz)
Ethyl
N-(N-benzyloxyleucyl)-.alpha.-[N-(3,5-di-tert-butyl-4hydroxybenzyl)carbamo
yl]glycinate
Brown oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.87 (3H, d, J=6.5
Hz), 0.89 (3H, d, J=6.5 Hz), 1.23 (2H, J=7 Hz), 1.20-1.55 (2H, m),
1.42 (18H, s), 1.55-1.75 (1H, m), 3.40-3.65 (1H, m), 4.20-4.50 (4H,
m), 4.65-4.80 (2H, m), 5.09 (0.5H, d, J=7 Hz), 5.10 (0.5H, d, J=7
Hz), 5.20 (1H, s), 5.62-5.78 (1H, br), 6.63 (1H, brt, J=5 Hz), 7.05
(2H, s), 7.30-7.45 (5H, m), 7.58 (0.5H, d, J=7 Hz), 7.78 (0.5H, d,
J=7 Hz)
Ethyl
N-(N-benzyloxyleucyl)-.alpha.-[4-(2-methoxyphenyl)-1-piperazinylcarbonyl]g
lycinate
Colorless oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.87 (3H, d, J=7
Hz), 0.90 (3H, d, J=7 Hz), 1.27 (3H, t, J=7 Hz), 1.30-1.55 (2H, m),
1.55-1.80 (1H, m), 3.00-3.25 (4H, m), 3.45-3.65 (1H, m), 3.75-4.10
(4H, m), 3.89 (3H, s), 4.23 (2H, q, J=7 Hz), 4.77 (0.8H, dd, J=12
Hz, J=19.5 Hz), 4.78 (1.2H, dd, J=12 Hz, J=19.5 Hz), 5.66 (1H, d,
J=7.5 Hz), 5.71 (0.4H, d, J=5 Hz), 5.78 (0.6H, d, J=6.5 Hz),
6.85-7.15 (4H, m), 7.30-7.50 (5H, m), 7.66 (0.6H, d, J=7.5 Hz),
7.81 (0.4H, d, J=7.5 Hz)
REFERENCE EXAMPLE 19
2.5 ml of 1N sodium hydroxide was added to 20 ml of a solution of
0.96 g of ethyl N-(N-benzyl-
oxyleucyl)-.alpha.-[N-3-methoxybenzyl)carbamoyl]glycinate in
ethanol, with ice-cooling. The mixture was stirred at room
temperature for 4 hours. The reaction mixture was diluted with 70
ml of water. The resulting solution was adjusted to pH 1 with
concentrated hydrochloric acid and extracted with ethyl acetate.
The extract was washed twice with an aqueous solution saturated
with sodium chloride, then dried with anhydrous magnesium sulfate,
and subjected to distillation to remove the solvent to obtain 1.03
g of
N-(N-benzyloxyleucyl)-.alpha.-[N-(3-methoxybenzyl)carbamoyl]glycine
as a white solid.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.84 (3H, d, J=6.5
Hz), 0.89 (3H, d, J=6.5 Hz), 1.25-1.50 (2H, m), 1.50-1.70 (1H, m),
3.50-3.70 (1H, m), 3.78 (3H, s), 4.10-4.22 (0.8 H, m), 4.35 (1.2H,
dd, J=6 Hz, J=12 Hz), 4.56 (0.8H, s), 4.60 (1.2H, s), 5.08-5.13
(0.4H, m), 5.14-5.23 (0.6H, m), 6.70-6.90 (2H, m), 7.15-7.40 (6H,
m), 7.63 (1H, brd, J=6 Hz)
REFERENCE EXAMPLE 20
The following compounds were obtained by using suitable starting
materials and by employing the same manner as in Reference Example
19.
N-(N-Benzyloxyleucyl)-2-[N-(2,4-dimethoxybenzyl)carbamoyl]glycine
Light yellow oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.80-0.95 (6H, m),
1.25-1.50 (2H, m), 1.50-1.75 (1H, m), 3.52 (0.5H, d, J=8 Hz), 3.63
(0.5H, dd, J=6 Hz, J=8.5 Hz), 3.76 (1.5H, s), 3.77 (1.5H, s), 3.78
(1.5H, s), 3.79 s), 4.31 (1H, d, J=5.5 Hz), 4.35 (1H, d, J=5.5 Hz),
4.57, 4.63 (each 1H, d, J=12.5 Hz), 5.02 (0.5H, d, J=6.5 Hz), 5.10
(0.5H, d, J=6.5 Hz), 5.10-6.20 (1H, br), 6.41 (1H, dd, J=l.5 Hz,
J=8 Hz), 6.42 (1H, d, J=1.5 Hz), 7.10 (0.5H, d, J=8 Hz), 7.12
(0.5H, d, J=8 Hz), 7.20-7.40 (5.5H, m), 7.52 (0.5H, d,
N- (N-benzyloxyleucyl)-.alpha.- [N-
(3,5-di-tert-butyl-4-hydroxybenzyl)carbamoyl]glycine
Brown oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.80-0.95 (6H, m),
1.30-1.50 (2H, m), 1.41 (18H, s), 1.55-1.70 (1H, m), 3.90-4.05 (1H,
m), 4.25-4.40 (2H, m), 4.45-4.60 (2H, m), 5.08 (0.5H, d, J=6.5 Hz),
5.13 (0.5H, d, J=6.5 Hz), 5.20 (1H, brs), 6.61 (0.5H, brt, J=6.5
Hz), 6.95-7.10 (2H, m), 7.14 (0.5H, brt, J=6.5 Hz), 7.20-7.40 (5H,
m), 7.71 (1H, brd, J=8.5 Hz)
N-(N-Benzyloxyleucyl)-.alpha.-[4-(2-methoxyphenyl)---piperazinylcarbonyl]gl
ycine
Yellow oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.85 (3H, d, J=6.5
Hz), 0.88 (3H, d, J=6.5 Hz), 1.35-1.55 (2H, m), 1.55=1.75 (1H, m),
2.95-3.25 (4H, m), 3.60 (1H, dd, J=5.5 Hz, J=8.5 Hz), 3.75-3.90
(4H, m), 3.86 (3H, s), 4.71 (1H, dd, J=2.5 Hz, J=2 Hz), 4.78 (1H,
dd, J=3.5 Hz, J=12 Hz), 5.59 (0.5H, d, J=7.5 Hz), 5.63 (0.5H, d,
J=12 Hz), 5.59 (0.5H, d, J=7.5 Hz), 5.63 (0.5H, d, J=7.5 Hz), 5.69
(2H, brs), 6.85-6.95 (3H, m), 6.95-7.10 (1H, m), 7.25-7.45 (5H, m),
8.00 (0.8 H, d, J=7.5 Hz), 8.06 (0.5H, d, J=7.5 Hz)
REFERENCE EXAMPLE 21
8.68 g of dicyclohexylcarbodiimide was added to 200 ml of a
solution of 8.73 g of 3-(3-indolyl)-2-hydroxyiminopropionic acid
and 4.83 g of N-hydroxysuccinimide in anhydrous dioxane, with
ice-cooling. The mixture was stirred at room temperature for 2
hours. The reaction mixture was filtered to remove the insoluble
materials, to obtain a brown solution. Separately, 5.6 ml of
triethylamine was added to 70 ml of a suspension of 7.27 g of
methyl L-leucinate hydrochloride in anhydrous dioxane. The mixture
was stirred at room temperature for 2 hours. Thereto was added the
above brown solution. The mixture was stirred for 16 hours. The
reaction mixture was diluted with 700 ml of ethyl acetate. The
resulting solution was washed with 1N hydrochloric acid, an aqueous
solution saturated with sodium chloride and an aqueous solution
saturated with sodium hydrogen carbonate in this order, then dried
with anhydrous magnesium sulfate, and subjected to distillation to
remove the solvent, to obtain 13.81 g of methyl
N-[2-hydroxyimino-3-(3-indolyl)propionyl]-L-leucinate as a brown
oily substance.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.87 (3H, d, J=6
Hz), 0.89 (3H, d, J=6 Hz), 1.45-1.75 (3H, m), 3.70 (3H, s), 4.08
(2H, s), 4.65 (1H, dt, J=5.5 Hz, J=8.5 Hz), 6.96 (1H, d, J=2.5 Hz),
7.09 (1H, d, J=7 Hz), 7.15 (1H, d, J=7 Hz), 7.26 (1H, d, J=7 Hz),
7.28 (1H, d, J=7 Hz), 7.78 (1H, d, J=7 Hz), 7.93 (1H, brs), 9.29
(1H, s)
REFERENCE EXAMPLE 22
The following compounds were obtained by using suitable starting
materials and by employing the same manner as in Reference Example
21.
Methyl N-[2-hydroxyimino-3-(3-indolyl)propionyl
]-L-phenylalaninate
Brown oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 3.01 (1H, dd, J=6
Hz, J=14 Hz), 3.09 (1H, dd, J=6 Hz, J=14 Hz), 3.65 (3H, s), 4.04,
4.11 (each 1H, d, J=14 Hz), 4.87 (1H, dt, J=6 Hz, J=8 Hz),
6.85-7.00 (2H, m), 7.04 (1H, d, J=2.5 Hz), 7.05-7.25 (6H, m), 7.30
(1H, d, J=7.5 Hz), 7.78 d, J=7.5 Hz), 8.00 (1H, brs), 8.56 (1H,
brs)
Methyl N-[2-hydroxyimino-3-(3-indolyl)propionyl]-L-methioninate
Brown oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 1.75-2.05 (1H, m),
1.98 (3H, s), 2.05-2.20 (1H, m), 2.40 (2H, t, J=7 Hz), 3.70 (3H,
s), 4.08 (2H, s), 4.74 (1H, dt, J=5.5 Hz, 8 Hz), 7.02 (1H, d, J=2.5
Hz), 7.08 (1H, t, J=8 Hz), 7.15 (1H, t, J=8 Hz), 7.26 (1H, d, J=8
Hz), 7.37 (1H, d, J=8 Hz), 7.78 (1H, d, J=8 Hz), 8.03 (1H, brs),
9.24 (1H, brs)
Methyl
0-benzyl-N-[2-hydroxyimino-3-(3-indolyl)-propionyl]-L-serinate
Light yellow foam-like substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 3.60 (1H, dd, J=3.5
Hz, J=9.5 Hz), 3.68 (3H, 3.60 (1H, dd, J=3.5 Hz, J=9.5 Hz), 4.06
(2H, brs), 4.36, 4.45 (each 1H, d, J=12 Hz), 4.76 (1H, dt, J=3.5
Hz, 8.5 Hz), 6.99 (1H, s), 7.05
7.35 (7H, m), 7.63 (1H, d, J=8 Hz), 7.78 d, J=7.5 Hz), 7.90 (1H,
brs), 8.89 (1H, brs)
Diethyl N-[2-hydroxyimino-3-(3-indolyl)propionyl]aminomalonate
Brown oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 1.24 (6H, t, J=7
Hz), 4.04 (2H, s), 4.10-4.35 (4H, m), 5.18 (1H, d, J=7 Hz), 6.98
(1H, d, J=2.5 Hz), 7.08 (1H, t, J=7 Hz), 7.14 (1H, t, J=7 Hz), 7.24
(1H, d, J=7 Hz), 7.77 (1H, d, J=7 Hz), 7.79 (1H, d, J=7 Hz), 8.05
(1H, brs), 9.30 (1H, brs)
Diethyl N-[2-hydroxyimino-3-(3-indolyl)propionyl]-L-aspartate
Brown oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 1.19 (3H, t, J=7
Hz), 1.20 (3H, t, J=7 Hz), 2.80 (1H, dd, J=5 Hz, J=17 Hz), 2.99
(1H, dd, J=5 Hz, J=17 Hz), 4.07 (2H, s), 4.17 (2H, q, J=7 Hz), 4.18
(2H, q, J=7 Hz), 4.87 (1H, dt, J=5 Hz, J=8.5 Hz), 7.07 (1H, d,
J=2.5 Hz), 7.12 (1H, t, J=7.5 Hz), 7.15 (1H, t, J=7 Hz), 7.28 (1H,
d, J=7 Hz), 7.67 (1H, d, J=8.5 Hz), 7.79 (1H, d, J=7.5 Hz), 8.03
(1H, brs), 8.58 (1H, s)
Methyl
O-benzyl-N-[2-hydroxyimino-3-(3-indolyl)propionyl]-L-tyrosinate
Brown oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 2.92 (1H, dd, J=6
Hz, J=14 Hz), 3.02 (1H, dd, J=6 Hz, J=14 Hz), 3.62 (3H, s), 4.10,
4.13 (each 1H, s), 4.81 (1H, dd, J=6 Hz, J=14 Hz), 4.88 (2H, s),
6.66, 6.78 (each 2H, d, J=8.5 Hz), 6.96 (1H, d, J=2 Hz), 7.09 (1H,
t, J=7.5 Hz), 7.15 (1H, t, J=7.5 Hz), 7.24 (1H, d, J=7 Hz),
7.25-7.45 (5H, m), 7.78 (1H, d, J=7 Hz), 8.06 (1H, brs)
Methyl N-[2-hydroxyimino-3-(3-indolyl)propionyl]-L-prolinate
Brown oily substance
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 1.30-1.55 (0.5H,
m), 1.55-1.95 (3H, m), 1.95-2.10 (0.5H, m), 3.20-3.45 (2H, m), 3.67
(3H, s), 4.00, 4.13 (each 0.7H, d, J=14.5 Hz), 4.18, 4.23 (each
0.3H, d, J=8 Hz), 4.40 (0.7H, dd, J=5.5 Hz, 8.5 Hz), 4.49 (0.3H,
brd, J=4.5 Hz), 7.00-7.20 (3H, m), 7.20-7.40 (1H, m), 7.70 (1H, d,
J=7 Hz), 8.43 (1H, brs), 9.47 (1H, s)
REFERENCE EXAMPLE 23
1.24 g of dicyclohexylcarbodiimide was added to 30 ml Of a solution
of 1.77 g of N-benzyloxy-DL-tryptophane and 0.70 g of
N-hydroxysuccinimide in anhydrous dioxane, with ice-cooling. The
mixture was stirred at room temperature for 2 hours. The reaction
mixture was filtered to remove the insoluble materials, whereby a
light brown solution was obtained. Separately, 0.8 ml of
triethylamine was added to 20 ml of a suspension of 0.89 g of
methyl L-serinate hydrochloride in anhydrous dioxane. The mixture
was stirred at room temperature for 2 hours. Thereto was added the
above light brown solution. The resulting mixture was stirred at
room temperature for 66 hours. The reaction mixture was diluted
with 200 ml of ethyl acetate. The resulting solution was washed
with 1N hydrochloric acid and an aqueous solution saturated with
sodium chloride, then dried with anhydrous magnesium sulfate, and
subjected to distillation to remove the solvent, to obtain 2.07 g
of methyl (N-benzyloxy-DL-tryptophyl)-L-serinate as a brown oily
substance.
.sup.1 H-NMR (DMSO-d.sub.6, 250 MHz) .delta. ppm: 2.70-2.87 (1H,
m), 2.97 (1H, dd, J=6 Hz, J=14.5 Hz), 3.45-3.80 (2H, m), 3.60, 3.61
(each 1.5H, s), 3.80-3.95 (1H, m), 4.30-4.55 (1H, m), 4.62 (2H, s),
5.08 (1H, dd, J=5.5 Hz, J=10.5 Hz), 6.49 (1H, d, J=7 Hz), 6.96 (1H,
t, J=7.5 Hz), 7.06 (1H, t, J=7.5 Hz), 7.13 (1H, s), 7.27 (5H, s),
7.32 (1H, d, J=7.5 Hz), 7.51 (1H, d, J=7.5 Hz), 8.15, 8.22 (each
0.5H, d, J=8 Hz), 10.83 (1H, brs)
EXAMPLE 1
1.09 g of dicyclohexylcarbodiimide was added to 25 ml of a solution
of 2.17 g of
(3RS,6SR)-3-benzyl-1-benzyloxy-3-carboxy-6-isobutylpiperazine-2,5-dione
and 0.63 g of N-hydroxysuccinimide in anhydrous dioxane. The
mixture was stirred at room temperature for 2 hours. Thereto was
added 0.80 g of 2-aminobenzothiazole. The mixture was stirred at
room temperature for 23 hours. The reaction mixture was diluted
with 200 ml of ethyl acetate. The resulting solution was washed
with an aqueous solution saturated with sodium hydrogen carbonate
and an aqueous solution saturated with sodium chloride, then dried
with anhydrous magnesium sulfate, and subjected to distillation to
remove the solvent. The residue was crystallized using ethyl
acetate, to obtain 2.77 g of
(3RS,6SR)-3-(benzothiazol-2-yl)-carbamoyl-3-benzyl-1-benzyloxy-6-isobutylp
iperazine-2,5-dione as a white solid.
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.75 (3H, d, J=6
Hz), 0.76 (3H, d, J=6 Hz), 1.50-1.85 (3H, m), 3.26, 3.64 (each 1H,
d, J=13.5 Hz), 3.51 (1H, t, J=6 Hz), 4.49, 4.81 (each 1H, d, J=10
Hz), 6.95 (1H, brs), 7.10-7.20 (2H, m), 7.25-7.40 (9H, m), 7.48
(1H, t, J=8 Hz), 7.85 (2H, t, J=8 Hz)
The compounds of Examples 27-29 and 31-39 described later were
obtained by using suitable starting materials and by employing the
same manner as in Example 1.
EXAMPLE 2
0.80 g of 10% palladium-carbon was added to 30 ml of a solution of
1.56 g of
(3RS,6SR)-3-(benzothiazol-2-yl)carbamoyl-3-benzyl-1-benzyloxy-6-isobuty
lpipera- zine-2,5-dione in dioxane. The mixture was stirred at room
temperature for 4 hours in a hydrogen current. The reaction mixture
was filtered to remove the catalyst. The filtrate was subjected to
distillation to remove the solvent. The resulting light brown oily
substance was recrystallized using dichloromethane, to obtain 0.56
g of
(3RS,6SR)-3-(benzothiazol-2-yl)carbamoyl-3-benzyl-1-hydroxy-6-isobutylpipe
razine-2,5-dione.
White solid
Melting point: 222-225.degree. C. (decomp.)
The compounds of Examples 9-26, 28-29, 33, 37-39, 47-62 and 64-65
described later were obtained by using suitable starting materials
and by employing the same manner as in Example 2.
EXAMPLE 3
In 20 ml of 1N hydrochloric acid (an ethanolic solution)was
dissolved 3.32 g of
(3RS,6SR)-1-(2-tetrahydropyranyloxy)-6-isobutyl-3-[N-(3-methoxybenzyl)carb
amoyl-3-methylpiperazine-2,5-dione. The solution was stirred for 5
minutes and then subjected to distillation to remove the solvent.
To the residue was added 30 ml of a 1N aqueous sodium hydroxide
solution. The mixture was washed with dichloromethane (30
ml.times.2) and diethyl ether (30 ml). The aqueous layer was
adjusted to pH 2-3 with concentrated hydrochloric acid and
extracted with ethyl acetate (30 ml.times.2). The extract was dried
with anhydrous magnesium sulfate and then subjected to distillation
to remove the solvent. The residue was recrystallized from diethyl
ether to obtain 1.26 g of
(3RS,6SR)-1-hydroxy-6-isobutyl-3-[N-(3-methoxybenzyl)]carbamoyl-3-methylpi
perazine-2,5-dione. Light brown solid Melting point:
151.5-153.5.degree. C.
EXAMPLE 4
13.21 g of dicyclohexylcarbodiimide was added to 500 ml of a
solution of 32.83 g of
N-(N-benzyloxyleucyl)-(3',5'-di-tert-butyl)tyrosine and 7.71 g of
N-hydroxysuccinimide in anhydrous dioxane. The mixture was stirred
at room temperature for 3 days and then kept at 120.degree. C. for
1.5 hours. The reaction mixture was allowed to cool. The resulting
insoluble materials were removed by filtration, and the filtrate
was concentrated to 200 ml under reduced pressure. The concentrate
was diluted With 1,000 ml of ethyl acetate. The resulting solution
was washed with 1N hydrochloric acid, an aqueous solution saturated
with sodium hydrogen carbonate and an aqueous solution saturated
with sodium chloride, then dried with anhydrous magnesium sulfate,
and subjected to vacuum distillation to remove the solvent. The
residue was purified by silica gel column chromatography (eluant:
ethyl acetate/n-hexane=1/2)to obtain 11.54 g of a compound (A) and
5.42 g of a compound (B).
Compound (A)
(3RS,6RS)-1-Benzyloxy-3-(3,5-di-tert-butyl-4-hydroxybenzyl)-6-isobutylpiper
azine-2,5-dione
Melting point: 198.5.degree.-200.5.degree. C. (decomp.)
(recrystallized from ethyl acetate)
Colorless needle-like crystals
Compound (B)
(3RS,
6SR)-1-Benzyloxy-3-(3,5-di-tert-butyl-4-hydroxybenzyl)-6-isobutylpiperazin
e-2,5-dione
Light yellow solid
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.86 (3H, d, J=6
Hz), 0.88 (3H, d, J=6 Hz), 1.43 (18H, s), 1.60-1.95 (3H, m), 2.74
(1H, dd, J=9.5 Hz, J=14 Hz), 3.44 (1H, dd, J=3.5 Hz, J=14 Hz), 3.77
(1H, t, J=6 Hz), 4.15 (1H, dd, J=3.5 Hz, J=9.5 Hz), 4.82, 4.97
(each 1H, d, J=10.5 Hz), 5.21 (1H, s), 5.67 (1H, brs), 7.01 (2H,
s), 7.37 (5H, s)
EXAMPLE 5
0.41 g of dicyclohexylcarbodiimide was added to 20 ml of a solution
of 0.91 g of
N-(N-benzyloxyleucyl)-.alpha.-[N-(3-methoxybenzyl)]carbamoylglycine
and 0.23 g of N-hydroxysuccinimide in anhydrous dioxane. The
mixture was stirred at room temperature for 16 hours. The reaction
mixture was filtered to remove the insoluble materials. The
filtrate was diluted with 50 ml of ethyl acetate. The resulting
solution was washed with 1N hydrochloric acid and an aqueous
solution saturated with sodium hydrogen carbonate, then dried with
anhydrous magnesium sulfate, and subjected to distillation to
remove the solvent, to obtain 0.81 g of
1-benzyloxy-6-isobutyl-3-[N-(3-methoxybenzyl)]carbamoylpiperazine-2,5-dion
e as a mixture of a cis form and a trans form.
Light brown solid
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.85 (1.5H, d,
J=6.5 Hz), 0.86 (1.5H, d, J=6.5 Hz), 0.92 (3H, d, J=6 Hz),
1.60-2.00 (3H, m), 3.78 (1.5H, s), 3.80 (1.5H, s), 4.00 (1H, t, J=6
Hz), 4.43 (1H, d, J=6 Hz), 4.46 (0.5H, d, J=6 Hz), 4.53 (0.5 H, d,
J=6 Hz), 4.54 (0.5H, s-like), 4.62 (0.5H, d, J=2.5 Hz), 4.88, 4.99
(each 0.5H, d, J=10.5 Hz), 4.95, 5.01 (each 0.5H, d, J=10.5 Hz),
6.46 (0.5H, brs), 6.90 (0.5H, brs), 6.70-7.00 (3H, m), 7.15-7.28
(1H, m), 7.37 (2.5H, s), 7.15-7.28 (1H, m), 7.37 (2.5H, s), 7.40
(2.5H, s), 7.54 (0.5H, brt, J=6 Hz), 8.53 (0.5H, brt, J=6 Hz)
EXAMPLE 6
7.00 g of N,N-carbonyldiimidazole was added to 200 ml of a solution
of 17.40 g of N-(N-benzyloxyleucyl)-(2', 4'-dimethoxy)phenylalanine
in anhydrous dioxane. The mixture was stirred at room temperature
for 16 hours. The reaction mixture was diluted with 1,000 ml of
ethyl acetate. The resulting solution was washed with 10% citric
acid, a 10% aqueous sodium hydrogen carbonate solution and an
aqueous solution saturated with sodium chloride in this order, then
dried with anhydrous magnesium sulfate, and subjected to vacuum
distillation to remove the solvent. The resulting yellow oily
substance was subjected to silica gel column chromatography
(eluant: ethyl acetate/n-hexane=1/1 - 3/1) to obtain 3.79 g of a
yellow vitreous compound (C)and 1.53 g of a light yellow solid
compound (D).
Compound (C)
(3RS,6RS)-1-Benzyloxy-3-(2,4-dimethoxybenzyl)-6-isobutylpiperazine-2,5-dion
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.84 (6H, d, J=6.5
Hz), 1.15-1.35 (1H, m), 1.40-1.55 (1H, m), 1.75-1.95 (1H, m), 2.92
(1H, dd, J=8 Hz, 13.5 Hz), 3.36 (1H dd, J=4.5 Hz, 13.5 Hz), 3.78
(3H, s), 3.80 (3H, s), 3.88 (1H, dd, J=5.5 Hz, 8 Hz), 4.20-4.35
(1H, m), 4.94, 5.02 (each 1H, d, J=10.5 Hz), 5.65 (1H, brs), 6.41
(1H, dd, J=2.5 Hz, J=8 Hz), 6.45 (1H, d, J=2.5 Hz), 7.04 (1H, d,
J=8 Hz), 7.30-7.50 (5H, m)
Compound (D)
(3RS,6SR)-1-Benzyloxy-3-(2,4-dimethoxybenzyl)-6-isobutylpiperazine-2,5dione
.sup.1 H-NMR (CDCl.sub.3, 250 MHz) .delta. ppm: 0.86 (3H, d, J=6.5
Hz), 0.87 (3H, d, J=6.5 Hz), 1.50-1.90 (3H, m), 2.93 (1H, dd, J=7.5
Hz, J=14 Hz), 3.51 (1H, dd, J=4 Hz, J=14 Hz), 3.75 (1H, t, J=6 Hz),
3.80 (3H, s), 3.85 (3H, s), 4.23 (1H, dd, J=4 Hz, 7.5 Hz), 4.82,
4.97 (each 1H, d, J=l1 Hz), 6.00 (1H, brs), 76.47 (1H, dd, J=2.5
Hz, J=8 Hz), 6.50 (1H, d, J=2.5 Hz), 7.15 (1H, d, J=8 Hz),
7.25-7.40 (5H, m)
EXAMPLE 7
150 ml of 7N hydrochloric acid. (an ethanolic solution)was dropwise
added, in 20 minutes at room temperature, to 150 ml of a solution
of 8.77 g of N-(2-hydroxyimino-4-methylpentanoyl)-L-phenylalanine
and 3.28 g of borane-trimethylamine in ethanol. The mixture was
stirred for 24 hours. The reaction mixture was subjected to vacuum
distillation at room temperature to remove the solvent. The residue
was dissolved in dichloromethane. The solution was washed with an
aqueous solution saturated with sodium chloride and an aqueous
solution saturated with sodium hydrogen carbonate, then dried with
anhydrous magnesium sulfate, and subjected to distillation to
remove the solvent. To the residue was added 100 ml of toluene. The
mixture was refluxed for 1 hour and then subjected to distillation
to remove the solvent. The resulting brown oily substance was
subjected to silica gel column chromatography (eluant:
dichloromethane/methanol=15/1) to obtain 1.77 g of a compound (E)
and 1.65 g of a compound (F).
Compound (E)
(3S, 6s)-3-benzyl-1-hydroxy-6-isobutylpiperazine-2,5-dione
Light orange prismatic crystals
Melting point: 152.degree.-153.degree. C. (recrystallized from
dichloromethane)
Compound (F)
(3S,6R)-3-Benzyl-1-hydroxy-6-isobutylpiperazine-2,5-dione
Light brown needle-like crystals
Melting point: 203.degree.-204.degree. C. (recrystallized from
chloroformdiethyl ether)
EXAMPLE 8
200 ml of 7N hydrochloric acid (an ethanolic solution)was added to
200 ml of a solution of 13.81 g of methyl
N-[2-hydroxyimino-3-(3-indolyl)propionyl]-L-leucinate and 4.51 g of
borane-trimethylamine in ethanol, with ice-cooling. The mixture was
stirred at room temperature for 16 hours. The reaction mixture was
subjected to distillation to remove the solvent. The residue was
mixed with 150 ml of dichloromethane and 150 ml of an aqueous
solution saturated with sodium hydrogen carbonate to conduct
distribution. The organic layer was dried with anhydrous magnesium
sulfate and then subjected to distillation to remove the solvent.
The residue was made into a toluene solution (100 ml). The solution
was refluxed for 1 hour and then subjected to distillation to
remove the solvent. 15.64 g of the resulting brown oily substance
was purified by silica gel column chromatography (eluant:
dichloromethane/methanol=50/1 -15/1) to obtain 1.28 g of a compound
(G) of cis form and 1.30 g of a compound (H) of trans form.
Compound (G)
(3S,6S)-1-Hydroxy-6-(3-indolylmethyl)-3-isobutylpiperazine-2,5-dione
Light orange solid
Melting point: 146.degree.-148.degree. C. (decomp.) (recrystallized
from chloroform-n-hexane)
Compound (H)
(3S,
6R)-1-Hydroxy-6-(3-indolylmethyl)-3-isobutylpiperazine-2,5-dione
Light orange solid
Melting point: 128.degree.-129.5.degree. C. (decomp.)
By using suitable starting materials and by employing the same
manners as in Examples 4, 5, 6 and 7, there were obtained the
compounds of Examples 9-45 shown in the following Tables 1-13.
TABLE 1 ______________________________________ ##STR14##
______________________________________ Example 9 Structures of
substituents ##STR15## R.sup.3 : H R.sup.4 : OH Configuration: 3S,
6S Crystal form: light orange prisms (recrystallized from
dichloromethane) Melting point: 152-153.degree. C. Salt form: free
Example 10 Structures of substituents ##STR16## R.sup.3 : H R.sup.4
: OH Configuration: 3S, 6R Crystal form: light brown needles
(recrystallized from chloroform-diethyl ether) Melting point:
203-204.degree. C. Salt form: free
______________________________________
TABLE 2 ______________________________________ Example 11
Structures of substituents ##STR17## R.sup.3 : H R.sup.4 : OH
Configuration: 3S, 6R Crystal form: colorless needles
(recrystallized from ethanol) Melting point: 243-245.degree. C.
Salt form: free Example 12 Structures of substituents ##STR18##
R.sup.3 : H R.sup.4 : OH Configuration: 3S, 6R Crystal form:
colorless needles (recrystallized from chloroform) Melting point:
155-158.degree. C. Salt form: free Example 13 Structures of
substituents ##STR19## R.sup.3 : H R.sup.4 : OH Configuration: 3RS,
6RS Crystal form: colorless needles (recrystallized from ethyl
acetate) Melting point: 219-221.degree. C. Salt form: free
______________________________________
TABLE 3 ______________________________________ Example 14
Structures of substituents ##STR20## R.sup.3 : H R.sup.4 : OH
Configuration: 3RS, 6SR Crystal form: colorless columns
(recrystallized from ethyl acetate) Melting point: 182-185.degree.
C. Salt form: free Example 15 Structures of substituents ##STR21##
R.sup.3 : H R.sup.4 : OH Configuration: 3RS, 6RS Crystal form:
light orange solid Melting point: 154-155.5.degree. C. Salt form:
free Example 16 Structures of substituents ##STR22## R.sup.3 : H
R.sup.4 : OH Configuration: 3RS, 6SR Crystal form: white solid
Melting point: 141.5-142.5.degree. C. Salt form: free
______________________________________
TABLE 4 ______________________________________ Example 17
Structures of substituents ##STR23## R.sup.3 : H R.sup.4 : OH
Configuration: 3RS, 6RS Crystal form: colorless prisms
(recrystallized from methanol-chloroform) Melting point:
216-216.5.degree. C. Salt form: free Example 18 Structures of
substituents ##STR24## R.sup.3 : H R.sup.4 : OH Configuration: 3RS,
6RS Crystal form: colorless prisms (recrystallized from isopropyl
alcohol-diisopropyl ether) Melting point: 117.5-119.degree. C. Salt
form: free Example 19 Structures of substituents ##STR25## R.sup.3
: H R.sup.4 : OH Configuration: 3RS, 6SR Crystal form: light orange
prisms (recrystallized from isopropyl alcohol-diisopropyl ether)
Melting point: 125-126.5.degree. C. Salt form: free
______________________________________
TABLE 5 ______________________________________ Example 20
Structures of substituents ##STR26## R.sup.3 : H R.sup.4 : OH
Configuration: 3S, 6S Crystal form: colorless needles
(recrystallized from methanol) Melting point: 234.5-241.degree. C.
Salt form: free Example 21 Structures of substituents ##STR27##
R.sup.3 : H R.sup.4 : OH Configuration: 3S, 6R Crystal form:
colorless needles (recrystallized from dichloromethane-methanol)
Melting point: 218-220.5.degree. C. Salt form: free Example 22
Structures of substituents ##STR28## R.sup.3 : H R.sup.4 : OH
Configuration: 3RS, 6RS Crystal form: colorless needles
(recrystallized from ethyl acetate) Melting point:
187-188.5.degree. C. Salt form: free
______________________________________
TABLE 6 ______________________________________ Example 23
Structures of substituents ##STR29## R.sup.3 : H R.sup.4 : OH
Configuration: 3S, 6S Crystal form: light brown solid Salt form:
free Example 24 Structures of substituents ##STR30## R.sup.3 : H
R.sup.4 : OH Configuration: 3S, 6R Crystal form: light brown solid
Salt form: free Example 25 Structures of substituents ##STR31##
R.sup.3 : H R.sup.4 : OH Configuration: 3S, 6S Crystal form: white
solid Salt form: free ______________________________________
TABLE 7 ______________________________________ Example 26
Structures of substituents ##STR32## R.sup.3 : H R.sup.4 : OH
Configuration: 3S, 6R Crystal form: colorless needles
(recrystallized from methanol) Melting point: 185.5-186.5.degree.
C. Salt form: free Example 27 Structures of substituents ##STR33##
##STR34## Configuration: 3RS, 6SR Crystal form: white solid Melting
point: 222-225.degree. C. (decompd.) Salt form: free Example 28
Structures of substituents ##STR35## ##STR36## Configuration: 3RS,
6SR Crystal form: white solid Melting point: 145-147.5.degree. C.
Salt form: free ______________________________________
TABLE 8 ______________________________________ Example 29
Structures of substituents ##STR37## R.sup.3 : CH.sub.3 R.sup.4 :
OH Configuration: 3RS, 6SR Crystal form: light brown solid Melting
point: 151.5-153.5.degree. C. Salt form: free Example 30 Structures
of substituents ##STR38## ##STR39## Configuration: 3RS, 6SR Crystal
form: white solid Salt form: free Example 31 Structures of
substituents ##STR40## ##STR41## Confiquration: 3RS, 6SR Crystal
form: white solid Salt form: free
______________________________________
TABLE 9 ______________________________________ Example 32
Structures of substituents ##STR42## ##STR43## Configuration:
Mixture of 3RS, 6SR and 3RS, 6RS Crystal form: light brown solid
Salt form: free Example 33 Structures of substituents ##STR44##
R.sup.3 : H R.sup.4 : OH Configuration: 3RS, 6SR Crystal form:
white solid (recrystallized from ethyl acetate-n-hexane) Melting
point: 141.5-143.5.degree. C. Salt form: free Example 34 Structures
of substituents ##STR45## ##STR46## Configuration: 3RS, 6SR Crystal
form: colorless prisms (recrystallized from diisopropyl ether) Salt
form: free ______________________________________
TABLE 10 ______________________________________ Example 35
Structures of substituents ##STR47## R.sup.3 : H ##STR48##
Configuration: Mixture of 3RS, 6SR and 3RS, 6RS Crystal form: white
solid (recrystallized from ethanol) Salt form: free Example 36
Structures of substituents ##STR49## R.sup.3 : H ##STR50##
Configuration: Mixture of 3RS, 6SR and 3RS, 6RS Crystal form: white
foam-like substance Salt form: free Example 37 Structures of
substituents ##STR51## R.sup.3 : H R.sup.4 : OH Configuration: 3RS,
6SR Crystal form: colorless needles (recrystallized from ethyl
acetate) Melting point: 140.5-141.5.degree. C. Salt form: free
______________________________________
TABLE 11 ______________________________________ Example 38
Structures of substituents ##STR52## R.sup.3 : H R.sup.4 : OH
Configuration: 3RS, 6SR Crystal form: colorless needles
(recrystallized from ethyl acetate-n-hexane) Melting point:
146.5-150.degree. C. Salt form: free Example 39 Structures of
substituents ##STR53## R.sup.3 : H R.sup.4 : OH Configuration: 3RS,
6SR Crystal form: colorless prisms (recrystallized from
ethanol-ethyl acetate) Melting point: 165-167.5.degree. C. Salt
form: hydrochloride Example 40 Structures of substituents ##STR54##
R.sup.3 : H ##STR55## Configuration: 3RS, 6RS Crystal form:
colorless needles (recrystallized from ethyl acetate) Melting
point: 198.5-200.5.degree. C. (decomp.) Salt form: free
______________________________________
TABLE 12 ______________________________________ Example 41
Structures of substituents ##STR56## R.sup.3 : H ##STR57##
Configuration: 3RS, 6SR Crystal form: light yellow solid Salt form:
free Example 42 Structures of substituents ##STR58## R.sup.3 : H
##STR59## Configuration: 3RS, 6RS Crystal form: light yellow
foam-like substance Salt form: free Example 43 Structures of
substituents ##STR60## R.sup.3 : H ##STR61## Configuration: 3RS,
6RS Crystal form: brown foam-like substance Salt form: free
______________________________________
TABLE 13 ______________________________________ Example 44
Structures of substituents ##STR62## ##STR63## Configuration: 3RS,
6RS Crystal form: yellow vitreous substance Salt form: free Example
45 Structures of substituents ##STR64## ##STR65## Configuration:
3RS, 6SR Crystal form: light yellow solid Salt form: free
______________________________________
EXAMPLE 46
1.24 g of dicyclohexylcarbodiimide was added to 30 ml of 2.04 g of
(3RS,6SR)-3-carboxy-6-isobutyl-3-methyl-1-(2-tetrahydropyranyloxy)piperazi
ne-2,5-dione and 0.73 g of N-hydroxysuccinimide in anhydrous
dioxane. The mixture was stirred at room temperature for 3 hours.
The reaction mixture was filtered to remove the insoluble
materials. To the filtrate was added 0.84 ml of
3-methoxybenzylamine. The mixture was stirred at room temperature
for 19 hours. The reaction mixture was diluted with 150 ml of ethyl
acetate. The resulting solution was washed with an aqueous solution
saturated with sodium hydrogencarbonate and an aqueous solution
saturated with sodium chloride, then dried with anhydrous magnesium
sulfate, and subjected to distillation to remove the solvent, to
obtain 3.32 g of
(3RS,6SR)-1-(2-tetrahydropyranyloxy)-6-isobutyl-3-[N-(3-methoxybenzyl)]car
bamoyl-3-methylpierazine-2,5-dione as a yellow oily substance.
By using suitable starting materials and by employing the same
manners as in Examples 4, 5, 6 and 8, there were obtained the
compounds of Examples 47-65 shown in the following Tables
14-19.
TABLE 14 ______________________________________ ##STR66##
______________________________________ Example 47 Structures of
substituents ##STR67## R.sup.8 : H R.sup.9 : OH Configuration: 2S,
6S Crystal form: light orange solid (recrystallized from
chloroform-n-hexane) Melting point: 146-148.degree. C. (decomp.)
Salt form: free Example 48 Structures of substituents ##STR68##
R.sup.8 : H R.sup.9 : OH Configuration: 3S, 6R Crystal form: light
orange solid Melting point: 128-129.5.degree. C. (decomp.) Salt
form: free ______________________________________
TABLE 15 ______________________________________ Example 49
Structures of substituents ##STR69## R.sup.8 : H R.sup.9 : OH
Configuration: 3S, 6S Crystal form: light orange solid
(recrystallized benzene) Melting point: 119-121.degree. C.
(decomp.) Salt form: free Example 50 Structures of substituents
##STR70## R.sup.8 : H R.sup.9 : OH Configuration: 3S, 6R Crystal
form: light orange solid (recrystallized from benzene) Melting
point: 219.5-222.degree. C. Salt form: free Example 51 Structures
of substituents R.sup.7 : CH.sub.2 CH.sub.2 SCH.sub.3 R.sup.8 : H
R.sup.9 : OH Configuration: 3S, 6S Crystal form: light brown solid
(recrystallized from benzene) Melting point: 129.5-134.5.degree. C.
(decomp.) Salt form: free Example 52 Structures of substituents
R.sup.7 : CH.sub.2 CH.sub.2 SCH.sub.3 R.sup.8 : H R.sup.9 : OH
Configuration: 3S, 6R Crystal form: light brown solid
(recrystallized from benzene) Melting point: 170.5-173.5.degree. C.
(decomp.) Salt form: free
______________________________________
TABLE 16 ______________________________________ Example 53
Structures of substituents ##STR71## R.sup.8 : H R.sup.9 : OH
Configuration: 3S, 6S Crystal form: white solid Melting point:
196-197.5.degree. C. (decomp.) Salt form: free Example 54
Structures of substituents ##STR72## R.sup.8 : H R.sup.9 : OH
Configuration: 3S, 6R Crystal form: orange solid (recrystallized
from benzene) Melting point: 180.5-182.degree. C. Salt form: free
Example 55 Structures of substituents R.sup.7 : COOC.sub.2 H.sub.5
R.sup.8 : H R.sup.9 : OH Configuration: 3RS, 6SR Crystal form:
white solid (recrystallized from dichloromethane-methanol) Melting
point: 166.5-167.5.degree. C. Salt form: free Example 56 Structures
of substituents R.sup.7 : CH.sub.2 COOC.sub.2 H.sub.5 R.sup.8 : H
R.sup.9 : OH Configuration: 3S, 6S Crystal form: colorless prisms
(recrystallized from isopropyl alcohol-diisopropyl ether) Melting
point: 183.5-185.5.degree. C. (decomp.) Salt form: free
______________________________________
TABLE 17 ______________________________________ Example 57
Structures of substituents R.sup.7 : CH.sub.2 COOC.sub.2 H.sub.5
R.sup.8 : H R.sup.9 : OH Configuration: 3S, 6R Crystal form: brown
prisms (recrystallized from isopropyl alcohol) Melting point:
172-172.5.degree. C. Salt form: free Example 58 Structures of
substituents ##STR73## R.sup.8 : H R.sup.9 : OH Configuration: 3S,
6S Crystal form: brown vitreous substance Salt form: free Example
59 Structures of substituents ##STR74## R.sup.8 : H R.sup.9 : OH
Configuration: 3S, 6R Crystal form: brown solid Salt form: free
Example 60 Structures of substituents ##STR75## R.sup.8 : H R.sup.9
: OH Configuration; 3S, 6S Crystal form: colorless vitreous
substance Salt form: free
______________________________________
TABLE 18 ______________________________________ Example 61
Structures of substituents ##STR76## R.sup.8 : H R.sup.9 : OH
Configuration: 3S, 6R Crystal form: white solid (recrystallized
from diethyl ether-n-hexane) Melting point: 188.5-191.5.degree. C.
(decomp.) Salt form: free Example 62 Structures of substituents
R.sup.7 : CH.sub.2 OH R.sup.8 : H R.sup.9 : OH Configuration: 3S,
6R Crystal form: light red solid (recrystallized from
dichloromethane) Melting point: 228.5-230.degree. C. (decomp.) Salt
form: free Example 63 Structures of substituents R.sup.7 : CH.sub.2
OH R.sup.8 : H ##STR77## Configuration: 3S, 6RS Crystal form: light
yellow foam-like substance Salt form: free
______________________________________
TABLE 19 ______________________________________ Example 64
Structures of substituents R.sup.7 & R.sup.8 :
--(CH.sub.2).sub.3 -- R.sup.9 : --OH Configuration: 3S, 6S Crystal
form: colorless columns (recrystallized from methanol) Melting
point: 238-241.degree. C. (decomp.) Salt form: free Example 65
Structures of substituents R.sup.7 : --CH.sub.2 OH R.sup.8 : H
R.sup.9 : --OH Configuration: 3S, 6S Crystal form: light yellow
foam-like substance Salt form: free
______________________________________
The NMR spectral data of part of the compounds obtained above are
shown in the following Tables 20-25.
TABLE 20 ______________________________________ Example Solvent
.sup.1 H--NMR (250 MHz) .delta. ppm
______________________________________ 23 DMSO-d.sub.6
0.30-0.50(1H, m), 0.62(3H, d, J=6Hz), 0.64(3H, d, J=6Hz), 0.70-0.85
(1H, m), 1.45-1.75(1H, m), 2.76(1H, dd, J=5Hz, J=14Hz), 3.06(1H,
dd, J=3Hz, J=14Hz), 3.71(1H, dd, J=5.5Hz, J=7.5Hz), 4.21(1H,
s-like), 5.00(2H, s), 6.91, 7.02(each 2H, d, J=8.5Hz),
7.25-7.50(5H, m), 8.26(1H, s), 9.91 (1H, s) 24 DMSO-d.sub.6
0.80(3H, d, J=6Hz), 0.82(3H, d, J=6Hz), 1.50-1.90(3H, m), 2.82(1H,
dd, J=4.5Hz, J=13.5Hz), 3.00-3.25(1H, m), 3.42(1H, t, J=5Hz),
4.29(1H, s- like), 5.03(2H, s), 6.88, 7.11(each 2H, d, J=8.5Hz),
7.25-7.55(5H, m), 8.25(1H, brs), 9.87(1H, s) 25 DMSO-d.sub.6
0.75(6H, d, J=6.5Hz), 1.00-1.20(2H, m), 1.20-1.40(1H, m), 2.88(2H,
d, J=5Hz), 3.88(1H, dd, J=5Hz, 6.5Hz), 4.10-4.15(1H, m), 5.13(2H,
s), 6.95 (1H, s), 7.20-7.45(5H, m), 7.81(1H, s), 8.13(1H, s),
10.12(1H, brs) 30 CDCl.sub.3 0.75(3H, d, J=6Hz), 0.76(3H, d,
J=6Hz), 1.50-1.85(3H, m), 3.26, 3.64 (each 1H, d, J=13.5Hz),
3.51(1H, t, J=6Hz), 4.49, 4.81(each 1H, d, J=10Hz), 6.95(1H, brs),
7.10-7.20 (2H, m), 7.25-7-40(9H, m), 7.48(1H, t, J=8Hz), 7.85(2H,
t, J=8Hz) ______________________________________
TABLE 21 ______________________________________ Example Solvent
.sup.1 H--NMR (250 MHz) .delta. ppm
______________________________________ 31 CDCl.sub.3 0.73(3H, d,
J=6Hz), 0.74(3H, d, J=6Hz), 1.55-1.70(3H, m), 3.15, 3.52 (each 1H,
d, J=13.5Hz), 3.46(1H, t, J=4.5Hz), 3.79(3H, s), 4.43(1H, dd,
J=5.5Hz, J=15Hz), 4.51(1H, dd, J=5.5Hz, J=15Hz), 4.35, 4.71(each
1H, d, J=10.5Hz), 6.75-6.95(4H, m), 7.05- 7.15(2H, m),
7.15-7.40(8H, m), 8.16 (1H, t, J=5.5Hz) 32 CDCl.sub.3 0.85(1.5H, d,
J=6.5Hz), 0.86(1.5H, d, J=6.5Hz), 0.92(3H, d, J=6Hz), 1.60-2.00(3H,
m), 3.78(1.5H, s), 3.80(1.5H, s), 4.00(1H, t, J=6Hz), 4.43(1H, d,
J=6Hz), 4.46(0.5H, d, J=6Hz), 4.53(0.5H, d, J=6Hz), 4.54 (0.5H,
s-like), 4.62(0.5H, d, J=2.5Hz), 4.88, 4.99(each 0.5H, d,
J=10.5Hz), 4.95, 5.01(each 0.5H, d, J=10.5Hz), 6.46(0.5H, brs),
6.90 (0.5H, brs), 6.70-7.00(3H, m), 7.15- 7.28(1H, m), 7.37(2.5H,
s), 7.40 (2.5H, s), 7.54(0.5H, brt, J=6Hz), 8.53(0.5H, brt, J=6Hz)
34 CDCl.sub.3 0.85(3H, d, J=6.5Hz), 0.86(3H, d, J=6Hz), 1.42(18H,
s), 1.65-1.75(2H, m), 1.75-1.95(1H, m), 4.00(1H, t, J=6Hz),
4.27(1H, dd, J=5Hz, J=14Hz), 4.45(1H, dd, J=6Hz, J=14Hz), 4.59 (1H,
d, J=2.5Hz), 4.94, 5.01(each 1H, d, J=10.5Hz), 5.21(1H, s),
6.33(1H, brs), 7.05(2H, s), 7.30-7.40(1H, br), 7.40(5H, s)
______________________________________
TABLE 22 ______________________________________ Example Solvent
.sup.1 H--NMR (250 MHz) .delta. ppm
______________________________________ 35 DMSO-d.sub.6
0.75-0.95(6H, m), 1.60-1.95(3H, m), 3.72(2.4H, s), 3.73(0.6H, s),
3.77 (0.6H, s), 3.79(2.4H, s), 4.00-4.30 (2H, m), 4.34(1H, t,
J=5Hz), 4.66 (1H, s-like), 4.80, 4.91(each 1H, d, J=10Hz), 6.46(1H,
dd, J=2.5Hz, J=8.5Hz), 6.54(1H, d, J=2.5Hz), 7.11 (0.2H, d,
J=8.5Hz), 7.20(0.8H, d, J=8.5Hz), 7.35-7.50(5H, m), 8.24 (0.2H,
brs), 8.44(0.2H, brs), 8.52 (0.8, brs), 8.66(0.8H, brt, J=6Hz) 36
CDCl.sub.3 0.90(3H, d, J=6Hz), 0.92(3H, d, J=6Hz), 1.65-2.15(3H,
m), 2.80-3.30 (4H, m), 3.50-3.65(1H, m), 3.65-3.85 (1H, m),
3.88(3H, s), 4.04(1H, t, J=6.5Hz), 3.95-4.35(2H, m), 4.95,
5.02(each 1H, d, J=10Hz), 5.16(1H, d, J=3Hz), 6.50-6.60(1H, m),
6.85- 7.00(3H, m), 7.00-7.15(1H, m), 7.30- 7.50(5H, m) 41
CDCl.sub.3 0.86(3H, d, J=6Hz), 0.88(3H, d, J=6Hz), 1.43(18H, s),
1.60-1.95(3H, m), 2.74(1H, dd, J=9.5Hz, J=14Hz), 3.44(1H, dd,
J=3.5Hz, J=14Hz), 3.77 (1H, t, J=6Hz), 4.15(1H, dd, J=3.5Hz,
J=9.5Hz), 4.82, 4.97(each 1H, d, J=10.5Hz), 5.21(1H, s), 5.67(1H,
brs), 7.01(2H, s), 7.37(5H, s)
______________________________________
TABLE 23 ______________________________________ Example Solvent
.sup.1 H--NMR (250 MHz) .delta. ppm
______________________________________ 42 CDCl.sub.3 0.81(3H, d,
J=6.5Hz), 0.82(3H, d, J=6.5Hz), 0.98-1.14(1H, m), 1.26-1.42 (1H,
m), 1.70-1.92(1H, m), 3.00(1H, dd, J=7.5Hz, J=14Hz), 3,14(1H, dd,
J=4Hz, J=14Hz), 3.85(6H, s), 3.79- 3.93(1H, m), 4.22-4.35(1H, m),
4.97, 5.03(each 1H, d, J=10.5Hz), 5.50(1H, s), 5.97-6.25(1H, br),
6.40(2H, s), 7.35-7.50(5H, m) 43 DMSO-d.sub.6 0.20-0.40(1H, m),
0.59(3H, d, J=6.5Hz), 0.61(3H, d, J=6.5Hz), 0.55- 0.70(1H, m),
1.35-1.55(1H, m), 2.06 (6H, s), 2.65(1H, dd, J=4.5Hz, J=14Hz),
2.99(1H, dd, J=3Hz, J=14Hz), 3.76(1H, t, J=6.5Hz), 4.22(1H, s-
like), 4.78, 4,92(each 1H, d, J=10Hz), 6.62(2H, s), 7.37(5H, s),
8.08(1H, s), 8.27(1H, brs) 44 CDCl.sub.3 0.84(6h, d, J=6.5Hz),
1.15-1.35(1H, m), 1.40-1.55(1H, m), 1.75-1.95(1H, m), 2.92(1H, dd,
J=8Hz, J=13.5Hz), 3.36(1H, dd, J=4.5Hz, J=13.5Hz), 3.78 (3H, s),
3.80(3H, s), 3.88(1H, dd, J=5.5Hz, J=8Hz), 4.20-4.35(1H, m), 4.94,
5.02(each 1H, d, J=10.5Hz), 5.65(1H, brs), 6.41(1H, dd, J=2.5Hz,
J=8Hz), 6.45(1H, d, J=2.5Hz), 7.04 (1H, d, J=8Hz), 7.30-7.50(5H, m)
______________________________________
TABLE 24 ______________________________________ Example Solvent
.sup.1 H--NMR (250 MHz) .delta. ppm
______________________________________ 45 CDCl.sub.3 0.86(3H, d,
J=6.5Hz), 0.87(3H, d, J=6.5Hz), 1.50-1.90(3H, m), 2.93(1H, dd,
J=7.5Hz, J=14Hz), 3.51(1H, dd, J=4Hz, J=14Hz), 3.75(1H, t, J=6Hz),
3.80(3H, s), 3.85(3H, s), 4.23(1H, dd, J=4Hz, J=7.5Hz), 4.82,
4.97(each 1H, d, J=11Hz), 6.00(1H, brs), 6.47 (1H, d, J=2.5Hz,
J=8Hz), 6.50(1H, d, J=2.5Hz), 7.15(1H, d, J=8Hz), 7.25- 7.40(5H, m)
58 DMSO-d.sub.6 0.80(1H, dd, J=9.5Hz, J=13Hz), 2.22 (1H, dd,
J=3.5Hz, J=13Hz), 3.00-3.55 (2H, m), 3.60-3.75(1H, m), 4.08, 4.13
(each 1H, d, J=3.5Hz), 4.30(1H, s- like), 6.19, 6.69(each 1H, d,
J=8.5Hz), 7.01(1H, t, J=7.5Hz), 7.10 (1H, t, J=7.5Hz), 7.17(1H, d,
J=2Hz), 7.25-7.50(6H, m), 7.56(1H, s), 7.57 (1H, d, J=8Hz),
10.22(1H, brs), 11.00 (1H, brs) 59 DMSO-d.sub.6 2.40-2.60(1H, m),
2.81(1H, d-like, J=4Hz), 2.87(1H, dd, J=4Hz, J=14Hz), 3.18(1H, dd,
J=4Hz, J=15Hz), 3.28 (1H, dd, J=4Hz, J=15Hz), 3.93(1H, s- like),
6.82, 6.97(each 2H, d, J=8.5Hz), 6.90-7.10(3H, m), 7.25-7.50 (6H,
m), 7.49(1H, d, J=8Hz), 7.94 (1H, s), 10.00(1H, s), 10.94(1H, brs)
______________________________________
TABLE 25 ______________________________________ Example Solvent
.sup.1 H--NMR (250 MHz) .delta. ppm
______________________________________ 60 DMSO-d.sub.6 0.75(1H, dd,
J=9.5Hz, J=13Hz), 2.21 (1H, dd, J=4Hz, J=13.5Hz), 3.08(1H, dd,
J=5Hz, J=15Hz), 3.15-3.30(1H, m), 3.55-3.75(1H, m), 4.28(1H,
s-like), 6.06, 6.44(each 2H, d, J=8,5Hz), 6.90-7.15(2H, m),
7.16(1H, s), 7.31 (1H, d, J=8Hz), 7.48(1H, d, J=2.5Hz), 7.57(1H, d,
J=8Hz), 9.08(1H, s), 10.21(1H, brs), 10.98(1H, brs) 63 CDCl.sub.3
1.65-1.70(0.5H, m), 2.37(0.5H, t, J=6Hz), 2.85-3.00(0.5H, m),
3.30-3.60 (3H, m), 3.70-3.85(0.5H, m), 4.21 (0.5H, s-like),
4.30(0.5H, s-like), 4.91, 5.04(each 1H, d, J=11Hz), 4.96, 5.13(each
1H, d, J=10.5Hz), 6.32 (0.5H, brs), 6.75(0.5H, brs), 6.95 (1H, d,
J=2Hz), 7.02(1H, t, J=7.5Hz), 7.11(1H, t, J=7.5Hz), 7.27(1H, d,
J=7.5Hz), 7.32-7.52(6H, m), 7.50-7.65 (1H, m), 8.77(1H, brs) 65
DMSO-d.sub.6 2.19(1H, dd, J=7Hz, 11Hz), 3.08(1H, dd, J=3Hz,
J=11Hz), 3.31(2H, d, J=4Hz), 3.60-3.75(1H, m), 4.32(1H, t, J=4Hz),
4.60(1H, brs), 6.93(1H, t, J=7.5Hz), 7.03(1H, t, J=5Hz), 7,07 (1H,
d, J=2Hz), 7.31(1H, d, J=8Hz), 7.52(1H, d, J=8Hz), 7.95(1H, brd.
J=2Hz), 10.03(1H, brs), 10.88(1H, brs)
______________________________________
Pharmacological Test--1
Inhibitory effect against superoxide radicals (O.sub.2.sup.-)
released from the peritoneal macrophage cells of guinea pig by
stimulation:
Mineral oil (15 ml)was intraperitoneally administered to a guinea
pig, then 96 hours after the administration, the peritoneal
macrophage cells were sampled.
Superoxide radicals (O.sub.2.sup.-) were determined by means of
reduction of cytochrome C method according to the procedure
described in an article written by T. Matsumoto, K. Takeshige and
S. Minakami: Biochemical and Biophysical Research Communications,
Vol. 88, No. 3, pp. 974-979, (1979).
Into 1 ml of 80 .mu.M-cytochrome C solution, the peritoneal
macrophage cells were added to make the final concentration of
2.times.10.sup.6 cells/ml, then each one of the test compounds of
the present invention was added thereto to make the test group
sample. On the other hand, water was added in place of the test
compound of the present invention to make the control group sample.
Each of the test group samples and the control group samples were
subjected to pre-incubation at 37.degree. C. for 1 minute.
As to the stimulating agent for releasing superoxide radicals
(O.sub.2.sup.-), FMLP (formylmethionyl leucyl phenylalanine)was
added to each one of the test sample solutions and the control
group samples to make the final concentration of FMLP to 10.sup.-7
M, then the sample solutions were subjected to additional reaction
by incubation for 1 minute.
Difference between the optical absorbances measured at 550 nm
(OD.sub.550) of both test group samples and control group samples
were determined, the 50% inhibitory concentration (IC.sub.50) was
obtained by calculating as the ratio of OD.sub.550 of the test
group sample to that of the control group sample. The IC.sub.50
(.times.10.sup.-5 g/ml) obtained from the test are shown in Table
26 as follows:
TABLE 26 ______________________________________ Test compound
IC.sub.50 Test compound IC.sub.50 No. (.times.10.sup.-5 g/ml) No.
(.times.10.sup.-5 g/ml) ______________________________________
Compound of: Compound of: Example 10 1.8 Example 28 0.3 Example 12
1.5 Example 29 0.3 Example 13 0.13 Example 47 1.0 Example 16 3.0
Example 49 1.0 Example 19 3.0 Example 51 0.3 Example 20 3.0 Example
52 0.6 Example 26 0.6 Example 53 3.0 Example 27 0.025 Example 60
1.0 ______________________________________
Pharmacological Test--2
Inhibitory effect against the releasing of lysozomal enzyme from
the neutrocytes of rat
The neutrocytes of rat were samples from the abdominal cavity of
rat 16 hours after the administration of 10 ml of 1% casein
solution (physiological saline solution).
Reaction of the releasing of lysozomal enzyme from the neutrocytes
of rat was determined by means of the method as described in an
article written by T. Matsumoto, K. Takeshige and S. Minakami:
Biochemical and Biophysical Research Communications, Vol. 88, No.
3, pp 974-979, (1979).
The neutrocytes being sampled were added to Hank's solution so as
to make the concentration thereof as 5.times.10.sup.5 cells/ml, the
test compound of piperazine derivative of the present invention was
added thereto to make the test group sample. On the other hand,
water was added in place of the piperazine derivative of the
present invention to make the control group sample. Each of the
test group samples and the control group samples were subjected to
pre-incubation at 37.degree. C. for 1 minute.
As to the stimulating agents, 10.sup.-6 M of FMLP (formylmethionyl
leucyl phenylalanine) and 5 .mu.g/ml of cytocharasin B solution
were added to the test solutions. Thus obtained mixture of the
solution was reacted by incubating for 15 minutes. After the
incubation, the mixture of the solution was subjected to
centrifugation at 2,000 rpm for 10 minutes. The supernatant (0.2
ml) was admixed with 0.5 ml of 0.1 M-acetic acid buffer solution
(pH 4.5) in which 0.2 mM of phenolphthalein glucuronic acid was
dissolved. Then the resulting mixture of the solution was reacted
at 37.degree. C. for 5 hours by incubation. After the reaction,
1N-NaOH solution was added to the reaction mixture so as to make
the pH value thereof to pH 8 to 9, and the optical absorbance of
both test group samples and control group samples were determined
at 540 nm (OD.sub.540).
The 50% inhibitory concentration (IC.sub.50) values were obtained
by calculation as the ratio of OD.sub.540 of the test group sample
to that of the control group sample. The IC.sub.50
(.times.10.sup.-5 g/ml) values obtained from the test are shown in
Table 27 below.
TABLE 27 ______________________________________ Test compound No.
IC.sub.50 (10.sup.-5 g/ml) ______________________________________
Compound of: Example 20 3.0 Example 27 0.3 Example 28 0.3 Example
29 0.2 ______________________________________
Pharmacological Test--3
Inhibitory effect against the releasing of hydrogen peroxide
(H.sub.2 O.sub.2) from the neutrocyte of abdominal cavity of
rat
1%-Casein solution was administered to the abdominal cavity of a
SD-strain rat, then 16 hours after the administration, the
neutrocytes were obtained by washing the abdominal cavity. Thus
obtained neutrocytes were washed with Hank's solution.
In to a reaction mixture consisting of the following
ingredients:
______________________________________ NaN.sub.3 1 mM NaCl 140 mM
KCl 5 mM MgCl.sub.2 1 mM CaCl.sub.2 1 mM Glucose 5.5 mM Phenol red
0.28 mM HRP (Horse Radish peroxide) 8.5 U/ml HEPES
[N-(2-Hydroxyethyl)pipera- 10 mM (pH 7.0) zine N'-2-ethanesulfonic
acid] Rat neutrocytes 10.sup.6 cells/ml FMLP 2 .times. 10.sup.-6 M
______________________________________
the test compound was added, then the whole mixture was incubated
at 37.degree. C. for 1 hour, and the mixture was subjected to a
centrifugal separation at 2,000 rpm for minutes. After the
centrifugal separation, 1 ml of the supernatant was sampled and 10
.mu.l of 1N-NaOH aqueous solution was added thereto. Then, the
optical absorbance at 610 nm (OD.sub.610) of the supernatant was
determined by means of using a spectro-photometer.
The IC.sub.50 (50% inhibitory concentration) of the test compound
was obtained by calculating as the ratio of OD.sub.610 of the test
group sample to that of the control group sample. The results are
indicated in Table 28 as follows:
TABLE 28 ______________________________________ Test compound
IC.sub.50 Test compound IC.sub.50 No. (10.sup.-5 g/ml) No.
(10.sup.-5 g/ml) ______________________________________ Compound
of: Compound of: Example 9 <0.6 Example 29 0.5 Example 11 0.6
Example 48 <0.3 Example 13 <0.5 Example 49 <0.3 Example 15
<0.3 Example 50 <0.3 Example 16 <0.3 Example 51 0.3
Example 17 <0.3 Example 54 0.3 Example 18 0.5 Example 55 0.3
Example 19 0.5 Example 57 0.3 Example 21 1.0 Example 60 0.6 Example
26 0.3 Example 64 <0.3
______________________________________
Pharmacological Test--4
Inhibitory effect against increase of urinary proteins in the
passive Heymann nephritis of rat
SD-strain male rats (7 week old, body weight: 200-230 g)were used
as test animals.
An antiserum which will induce passive Heymann nephritis of rat was
prepared by procedures according to the method of T. S. Edington,
et al. [T. S. Edington, R. J. Glassock and F. J. Dixon: Autologous
immune complex nephritis induced with renal tublar antigen. I.
Identification and isolation of the pathogenetic antigen. Journal
of Experimental Medicine Vol. 127, pp. 555-572 (1968).] as
follows:
At the first, an antigen (FX1A fraction) of the renaltublar brush
border was sampled from the SD rat. Next, the antigen was admixed
with Freund' complete adjuvant, then a New Zealand White rabbit was
sensitized therewith. The sensitization procedures were conducted 3
times in every 2 weeks, and 2 weeks after the final sensitization,
the blood sample was obtained from the rabbit.
The test rats were divided into test groups depend on their body
weight, each of which is consisting of 7 rats.
Heymann nephritis of the rats were induced by injecting the
above-mentioned antiserum to the tail vein of the test rats. Each
one of the test compounds was suspended in 0.5%-CMC
(carboxymethylcellulose) aqueous solution, and said test compound
suspension was orally administered once a day from the fourth day
after the injection, for 7 days continuously. The urine samples of
the rat were taken in time sequentially from the 10th day after the
injection, and the amount of urinary protein in the samples were
determined. The rate of inhibitory effect (%) against the
production of urinary protein performed by the test compound was
calculated by the formula as follows:
wherein
A: the amount of urinary protein in the control group;
B: the amount of urinary protein in the test group (in the case
that test compound was administered).
The test results are shown in Table 29 as follows:
TABLE 29 ______________________________________ Rate of inhibitory
Test compound Dose effect (%) No. (mg/kg/day) (12th day)
______________________________________ Compound of: Example 13 20
57.8 .+-. 6.1 Example 57 5 53.1 .+-. 15.1
______________________________________
Pharmacological Test--5
Inhibitory effects on rat mesangial cell proliferation
The kidney of SD-strain rat was aseptically taken out by excision.
and the renal cortex was cut out therefrom. The renal glomeruli
were isolated by use of sieve. The glomeruli were cultivated in
RPMI1640 culture medium [which contains 10% of FBS (fetal bovine
serum)] for 4 weeks. Thus obtained cells were used as mesangial
cells.
An experiment of incorporation of thymidine by interleukin-1.beta.
was conducted by procedures according to the method of Ganz
[Michael B. Ganz; Mary C. Perfetto and Walter F. Boron: American
Journal of Physiology, Vol. 259, F269-F278, (1990)]. Thus,
2.times.10.sup.4 cells/ml of mesangial cells were scattered on a
48-well plate (0.5 ml/well), and the cells were cultivated in RPMI
culture medium (which contains 10% of FBS) for 3 days. Then, the
culture medium was changed to another RPMI culture medium in which
the concentration of FBS was decreased from 10% to 0.5% and
cultivated for 3 days. Next, the RPMI culture medium (containing
0.5% of FBS) was changed to other RPMI culture medium to which the
test compound and 1 ng/ml of interleukin-1.beta. were added. The
cultivation was conducted for 24 hours, then 1 .mu.Ci/well of
3H-thymidine was added to the culture medium, and the cultivation
was continued for additional 24 hours.
The amount of .sup.3 H-thymidine being incorporated into the
mesangial cells was measured by use of a scintillation counter, and
the rate of inhibition (%) in comparison of the test group vs.
control group was calculated by the following formula:
wherein
C: the incorporated amount of .sup.3 H-thymidine in control
group;
D: the incorporated amount of .sup.3 H-thymidine in the case of
that test compound was added;
E: the incorporated amount of .sup.3 H-thymidine in the case of
that interleukin-1.beta. was not added.
The test results are shown in the following Table 30.
TABLE 30 ______________________________________ Rate of inhibition
Test compound Concentration (%)
______________________________________ Compound of: Example 13 10
.mu.g/ml 121.5 .+-. 6.1 3 .mu.g/ml 77.9 .+-. 8.3 Example 57 10
.mu.g/ml 56.7 .+-. 2.9 3 .mu.g/ml 26.3 .+-. 5.8
______________________________________
* * * * *